Mechanisms Associated with PINK1 Variants in Parkinson's Disease

Hanliang Dan; Xiaohui Huang; Zheng Liu; Bing Wei; Maslinda Musa

doi:10.12688/f1000research.170090.2

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Review

Revised

Mechanisms Associated with PINK1 Variants in Parkinson's Disease

[version 2; peer review: 1 approved, 1 approved with reservations, 1 not approved]

Previously titled : "Mechanisms Associated with PINK1 Mutations in Parkinson's Disease"

Hanliang Dan^1-3^*, Xiaohui Huang⁴^*, Zheng Liu ⁴, Bing Wei⁵, Maslinda Musa^1,2

Hanliang Dan^1-3^*, Xiaohui Huang⁴^*, [...] Zheng Liu ⁴, Bing Wei⁵, Maslinda Musa^1,2

^* Equal contributors

PUBLISHED 22 Apr 2026

Author details Author details

¹ School of Biology, Faculty of Applied Sciences, Universiti Teknologi MARA, UiTM, Shah Alam Seksyen 2, 40450 Selangor, Malaysia
² Centre for Chemical Synthesis and Polymer Technology, Institute of Science, Universiti Teknologi MARA, UiTM, Shah Alam Seksyen 2, 40450 Selangor, Malaysia
³ Nanxishan Hospital of Guangxi Zhuang Autonomous Region (The Second People's Hospital of Guangxi Zhuang Autonomous Region), Guilin, Guangxi 541002, China
⁴ Guangxi Key Laboratory of Multimodal Biomarkers and Precision Diagnosis, College of Medical Laboratory and Biotechnology, Guilin Medical University, Guilin, Guangxi, 541004, China
⁵ Guilin Medical University, Guangxi Key Laboratory of Tumor Immunology and Microenvironment Regulation, Department of Basic Medicine, Guilin, Guangxi 541004, China

Hanliang Dan
Roles: Conceptualization, Investigation, Methodology, Writing – Original Draft Preparation

Xiaohui Huang
Roles: Conceptualization, Investigation, Methodology, Writing – Original Draft Preparation

Zheng Liu
Roles: Conceptualization, Writing – Original Draft Preparation, Writing – Review & Editing

Bing Wei
Roles: Conceptualization, Investigation, Writing – Review & Editing

Maslinda Musa
Roles: Conceptualization, Supervision, Writing – Original Draft Preparation, Writing – Review & Editing

OPEN PEER REVIEW

REVIEWER STATUS

This article is included in the Genomics and Genetics gateway.

This article is included in the Cell & Molecular Biology gateway.

Abstract

Parkinson’s disease (PD) is a widespread and progressively debilitating neurodegenerative disorder with a growing global prevalence. While most cases are sporadic, loss-of-function variants in the PINK1 gene are a primary cause of autosomal recessive early-onset PD. This review critically explores the molecular mechanisms linking PINK1 dysfunction to PD, with a specific focus on the kinase’s role in phosphorylating Ubiquitin and Parkin at the conserved Serine 65 (Ser65) residue. We discuss how this phosphorylation event acts as a molecular switch to recruit the novel autophagy receptors Optineurin (OPTN) and NDP52, thereby initiating mitophagy—a process often disrupted by pathogenic variants. Furthermore, we examine the emerging role of PINK1 in suppressing neuroinflammation via the STING pathway and evaluate the translational potential of targeting these molecular checkpoints for therapeutic intervention. These insights lay the groundwork for developing precision medicine strategies to address the urgent need for effective PD treatments.

Keywords

Parkinson's disease, PINK1, genetic mutation, mitochondrial phosphorylation, autophagy pathways, oxidative stress

Corresponding authors: Zheng Liu, Bing Wei, Maslinda Musa

Competing interests: No competing interests were disclosed.

Grant information: The author(s) declared that no grants were involved in supporting this work.

Copyright: © 2026 Dan H et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

How to cite: Dan H, Huang X, Liu Z et al. Mechanisms Associated with PINK1 Variants in Parkinson's Disease [version 2; peer review: 1 approved, 1 approved with reservations, 1 not approved]. F1000Research 2026, 14:1138 (https://doi.org/10.12688/f1000research.170090.2) First published: 20 Oct 2025, 14:1138 (https://doi.org/10.12688/f1000research.170090.1) Latest published: 18 Jun 2026, 14:1138 (https://doi.org/10.12688/f1000research.170090.3)

Revised Amendments from Version 1

We are pleased to present this revised review on PINK1-linked Parkinson's disease (PD), significantly improved following constructive peer review.

In response to reviewer feedback, we have transformed the manuscript from a descriptive summary into a critical, forward-looking analysis. Key revisions include: (1) refining the Introduction to explicitly define knowledge gaps, particularly PINK1's emerging role in innate immunity and neuroinflammation via the cGAS-STING pathway; (2) deepening mechanistic discussions to clarify how specific pathogenic variants disrupt Ser65 phosphorylation, blocking recruitment of the primary autophagy receptors OPTN and NDP52; and (3) adding a dedicated section on therapeutic implications, evaluating precision strategies such as kinase amplification with Kinetin and USP30 inhibition.

These revisions position PINK1 not merely as a regulator of mitophagy, but as a critical intersection point between mitochondrial quality control and immune signaling. By integrating contemporary discoveries with translational insights, we offer a framework that we hope will inspire new research directions and accelerate therapeutic development. We are grateful to the reviewers for their rigorous engagement, which has been instrumental in shaping this final version.

See the authors' detailed response to the review by Ryan L Davis
See the authors' detailed response to the review by Eman Ezzeldien Mohamed
See the authors' detailed response to the review by DOMENICO PRATICO

1. Introduction

Parkinson’s disease (PD) is the second most prevalent neurodegenerative disorder worldwide, characterized by the progressive loss of dopaminergic neurons in the substantia nigra pars compacta. According to recent epidemiological data, the global prevalence of PD has more than doubled over the past two decades, a trend largely attributed to aging populations.¹^,² While the majority of cases are idiopathic, approximately 5–10% of patients exhibit monogenic inheritance. Among these, loss-of-function variants in the PINK1 gene (PTEN-induced kinase 1; HGNC:14581) are established as a primary cause of autosomal recessive early-onset PD (EOPD). Although PINK1-related PD represents a subset of the total patient population, elucidating its role is critical for understanding the mitochondrial quality control failure that characterizes both familial and sporadic forms of the disease.³

The clinical hallmark of PD is the progressive degeneration of dopaminergic neurons within the substantia nigra pars compacta, leading to classic motor symptoms such as bradykinesia, resting tremor, and rigidity.⁴ However, it is increasingly recognized that a prolonged prodromal phase, characterized by non-motor symptoms including hyposmia, sleep disturbances, and depression, often precedes motor onset by decades.⁵ In the context of PINK1-linked PD, the clinical phenotype typically manifests as early-onset Parkinsonism, frequently occurring before the age of 45.³ Notably, patients with PINK1 variants often exhibit a slower disease progression and a sustained, robust response to levodopa compared to those with late-onset sporadic PD.⁶ Understanding these distinct clinical trajectories is crucial for accurate prognosis and personalized patient management.

The PINK1 gene encodes a 581-amino acid protein that is broadly expressed and structurally composed of an N-terminal mitochondrial targeting sequence, a transmembrane domain, and a C-terminal serine/threonine kinase domain.⁷ While loss-of-function variants in PINK1 are widely recognized for impairing mitochondrial protection against oxidative stress,⁸ the precise molecular cascade linking these deficits to clinical neurodegeneration remains incompletely mapped. Specifically, there is a critical knowledge gap regarding how PINK1 dysfunction extends beyond canonical mitophagy to affect broader cellular processes such as innate immunity and proteostasis.⁹ Moreover, despite extensive mechanistic studies, translating these findings into effective therapeutics has proven difficult. Therefore, the objective of this review is to critically examine the multifaceted mechanisms of PINK1-driven pathogenesis—moving beyond classical mitophagy—and to evaluate the translational potential of targeting this pathway for PD intervention.

2. The diversity of PINK1 mutations

Under basal physiological conditions, the cellular levels of PINK1 are maintained at an exceptionally low limit through a rapid and constitutive turnover mechanism. The PINK1 precursor is imported into healthy, polarized mitochondria via the translocase of the outer membrane (TOM) and translocase of the inner membrane (TIM) complexes.¹⁰ Upon reaching the inner mitochondrial membrane (IMM), the N-terminal mitochondrial targeting sequence (MTS) is first cleaved by the mitochondrial processing peptidase (MPP). Subsequently, the transmembrane domain is cleaved by the rhomboid protease PARL (presenilin-associated rhomboid-like) between Alanine-103 and Phenylalanine-104.¹¹ This proteolytic processing generates a truncated, unstable form of PINK1, which is retro-translocated to the cytosol and rapidly degraded by the ubiquitin-proteasome system via the N-end rule pathway.¹² However, this homeostatic cycle is intimately coupled to mitochondrial bioenergetics. When mitochondria sustain damage and lose their membrane potential (Δψm), the TIM23-mediated import of PINK1 is arrested. Consequently, full-length PINK1 stabilizes on the outer mitochondrial membrane (OMM) with its kinase domain facing the cytosol.¹³ This accumulation promotes PINK1 homodimerization and trans-autophosphorylation at Serine 228 and Serine 402, events that are requisite for maximizing its kinase activity and initiating the downstream recruitment of Parkin.¹⁴ Thus, PINK1 functions as a molecular sensor of mitochondrial quality, converting bioenergetic stress into a distinct phosphorylation signal.

3. The diversity of PINK1 pathogenic variants

The integrity of the mitochondrial quality control system is fundamentally dependent on the precise catalytic activity of PINK1. Consequently, pathogenic variants in the PINK1 gene predominantly result in a loss of function, disrupting the neuroprotective response described in the previous section. Since the initial identification of the G309D missense variant and the W437X truncation in the PARK6 pedigree by Valente et al.,¹⁵ over 70 distinct pathogenic variants have been cataloged. Structurally, these variants are not randomly distributed but are heavily clustered within the highly conserved serine/threonine kinase domain (residues 156–509), underscoring the critical importance of kinase activity for neuroprotection.¹⁶

Mechanistically, these variants impair PINK1 function through distinct molecular deficits. A significant proportion of missense variants, such as G309D, L347P, and G409V, induce kinase inactivation by destabilizing the ATP-binding pocket or the catalytic loop. This structural compromise abolishes the essential autophosphorylation events (e.g., at Ser228 and Ser402) required for the recruitment of Parkin.¹⁷ Beyond catalytic inactivation, protein instability represents another major pathogenic mechanism. Truncation variants, including W437X and Q456X, often result in the rapid degradation of the transcript via the nonsense-mediated decay pathway or produce unstable protein fragments that fail to accumulate on the outer mitochondrial membrane, even under conditions of cellular stress.¹⁸ Furthermore, rare variants located in the N-terminal mitochondrial targeting sequence have been observed to interfere with the efficient import of PINK1 into mitochondria, thereby preventing its correct subcellular localization.¹⁹

Collectively, regardless of whether the defect is kinetic (kinase dead) or structural (instability), these perturbations converge on a common pathological outcome: the failure to sense mitochondrial depolarization. This sensory defect prevents the initiation of mitophagy, leading to the progressive accumulation of dysfunctional organelles within dopaminergic neurons.

Figure 1. (A) Healthy Mitochondria (Basal Turnover): Under physiological conditions, PINK1 is constitutively imported into the inner mitochondrial membrane via the TOM/TIM complex. It is processed by the mitochondrial processing peptidase (MPP) and the rhomboid protease PARL, generating cleaved fragments that are rapidly degraded by the proteasome. This continuous turnover maintains low levels of PINK1, keeping Parkin inactive in the cytosol. (B) Damaged Mitochondria (Mitophagy Initiation): Upon mitochondrial damage (loss of membrane potential (Δψm), PINK1 import is arrested, leading to the accumulation of full-length PINK1 on the outer mitochondrial membrane (OMM). Stabilized PINK1 phosphorylates both Parkin and Ubiquitin (Ub) at the conserved Serine 65 (Ser65) residue. Phosphorylated Ubiquitin (p-Ub) serves as a signal to recruit the primary autophagy receptors Optineurin (OPTN) and NDP52. These receptors bridge the ubiquitinated mitochondria to the autophagosome via LC3, initiating mitophagy. (C) Pathogenic PINK1 Variant (Disease State): Pathogenic variants (e.g., G309D) located in the kinase domain impair the catalytic activity of PINK1. Consequently, PINK1 fails to phosphorylate Ubiquitin and Parkin even under stress conditions. The absence of p-Ub prevents the recruitment of OPTN and NDP52, blocking the formation of the autophagosome. This failure in quality control leads to the accumulation of damaged, ROS-producing mitochondria, ultimately driving dopaminergic neurodegeneration.

4. PINK1 and the pathogenesis of PD

4.1 PINK1 variants impair phosphorylation of downstream substrates

Investigating the interplay between PINK1 kinase activity and its substrates provides crucial insights into PD pathogenesis. Contrary to earlier assumptions that PINK1 broadly phosphorylates mitochondria, it targets specific proteins to mediate neuroprotection. Early studies identified the mitochondrial chaperone TRAP1 and the serine protease HtrA2/OMI as potential substrates. Pridgeon et al. demonstrated that PINK1 phosphorylates TRAP1 to suppress oxidative stress, a function abolished by the G309D variant.⁸ Similarly, PINK1-dependent phosphorylation of HtrA2 enhances its protease activity, conferring resistance to cellular stress.²⁰

However, the most significant breakthrough has been the identification of Parkin and Ubiquitin as the physiological substrates of PINK1. Under stress, PINK1 phosphorylates both the ubiquitin-like (UBL) domain of Parkin and Ubiquitin itself at the conserved Serine 65 (Ser65) residue.²¹^,²² This dual phosphorylation event is the molecular switch that activates Parkin’s E3 ligase activity (Figure 1). Crucially, pathogenic variants such as G309D and L347P fail to phosphorylate Ubiquitin or Parkin at Ser65, thereby locking Parkin in an auto-inhibited state and completely blocking the downstream quality control cascade.²³

4.2 Disruption of mitophagy: The role of OPTN and NDP52

Mitophagy, the selective degradation of damaged mitochondria, is the central pathway regulated by PINK1. In the absence of functional PINK1, this clearance mechanism fails. While early models suggested that p62/SQSTM1 was the primary autophagy receptor linking ubiquitinated mitochondria to the autophagosome, recent evidence has redefined this model.

Current consensus indicates that Optineurin (OPTN) and NDP52 (CALCOCO2) are the primary autophagy receptors recruited by PINK1/Parkin-mediated ubiquitin chains.²⁴ These receptors bind to the ubiquitinated outer mitochondrial membrane and recruit the autophagy machinery via their LC3-interacting regions. Importantly, PINK1 further enhances this process by phosphorylating ubiquitin chains, which serves as a “eat-me” signal that selectively recruits OPTN and NDP52.²⁵ Pathogenic PINK1 variants disrupt this recruitment hierarchy. Without the initial phosphorylation trigger from PINK1, Parkin is not activated, ubiquitin chains are not formed, and OPTN/NDP52 cannot engage the autophagy machinery. Consequently, damaged mitochondria accumulate, releasing toxic byproducts that drive dopaminergic neurodegeneration.

4.3 Beyond mitophagy: PINK1 and neuroinflammation

Emerging evidence suggests that the consequences of PINK1 dysfunction extend beyond defective mitophagy to include aberrant innate immune signaling. Under physiological conditions, mitophagy prevents the leakage of mitochondrial DNA (mtDNA) into the cytosol. However, in the absence of PINK1, damaged mitochondria accumulate and release mtDNA, which is sensed by the cGAS-STING pathway. This triggers a robust Type I interferon response and the release of pro-inflammatory cytokines such as Interleukin-6 (IL-6).²⁶ Crucially, Matheoud et al. demonstrated that intestinal infection with Gram-negative bacteria in Pink1-knockout mice engages mitochondrial antigen presentation and autoimmune mechanisms, highlighting the gut-brain axis and inflammation as key drivers of pathogenesis.²⁷ Clinically, elevated serum IL-6 levels have been reported in patients with PINK1 or PRKN variants, correlating with disease progression.²⁸ This suggests that PINK1 functions not only as a quality control sensor but also as a critical immunological checkpoint.

4.4 Therapeutic implications

Given that PINK1 loss-of-function drives PD, pharmacological strategies to amplify PINK1 activity or bypass its function are being actively explored. One approach involves the neo-substrate Kinetin (N6-furfuryladenine) and its riboside prodrugs, which have been shown to accelerate PINK1 activation and enhance Parkin recruitment in neuronal cells independent of mitochondrial depolarization.²⁹^,³⁰ Additionally, inhibitors of the deubiquitinase USP30, which opposes PINK1/Parkin signaling by removing ubiquitin chains from mitochondria, have shown promise in preclinical models by restoring mitophagy flux.³¹ Recent studies highlight that USP30 inhibition can rescue mitophagy defects even in the presence of certain pathogenic variants, making it a viable therapeutic target.³² These targeted approaches represent the frontier of precision medicine for PINK1-linked Parkinson’s disease.

5. Conclusions

In summary, this review highlights the intricate relationship between PINK1 loss-of-function variants and the pathogenesis of Parkinson’s disease. The recent identification of Optineurin (OPTN) and NDP52 as the primary autophagy receptors recruited by PINK1-phosphorylated ubiquitin chains has redefined our understanding of mitophagy. Pathogenic variants, by failing to execute the critical Ser65 phosphorylation step, block this recruitment hierarchy, leading to the accumulation of damaged mitochondria. Beyond bioenergetic failure, recent evidence underscores that this defect triggers the cGAS-STING pathway, driving neuroinflammation as a key component of disease progression. A deeper understanding of these mechanisms identifies specific therapeutic targets—such as amplifying PINK1 kinase activity with Kinetin or inhibiting the deubiquitinase USP30—offering promising new avenues for clinical intervention in Parkinson’s disease.

Data availability

No data are associated with this article.

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Version 3

VERSION 3 PUBLISHED 20 Oct 2025

Author details Author details

Hanliang Dan
Roles: Conceptualization, Investigation, Methodology, Writing – Original Draft Preparation

Xiaohui Huang
Roles: Conceptualization, Investigation, Methodology, Writing – Original Draft Preparation

Zheng Liu
Roles: Conceptualization, Writing – Original Draft Preparation, Writing – Review & Editing

Bing Wei
Roles: Conceptualization, Investigation, Writing – Review & Editing

Maslinda Musa
Roles: Conceptualization, Supervision, Writing – Original Draft Preparation, Writing – Review & Editing

Competing interests

No competing interests were disclosed.

Grant information

The author(s) declared that no grants were involved in supporting this work.

Article Versions (3)

version 3

Revised

Published: 18 Jun 2026, 14:1138

https://doi.org/10.12688/f1000research.170090.3

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Published: 22 Apr 2026, 14:1138

https://doi.org/10.12688/f1000research.170090.2

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Published: 20 Oct 2025, 14:1138

https://doi.org/10.12688/f1000research.170090.1

© 2026 Dan H et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

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Dan H, Huang X, Liu Z et al. Mechanisms Associated with PINK1 Variants in Parkinson's Disease [version 2; peer review: 1 approved, 1 approved with reservations, 1 not approved]. F1000Research 2026, 14:1138 (https://doi.org/10.12688/f1000research.170090.2)

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Reviewer Report 25 May 2026

DOMENICO PRATICO, Department of Neural Sciences, Lewis Katz School of Medicine at Temple University, Philadelphia, Pennsylvania, USA

Approved with Reservations

https://doi.org/10.5256/f1000research.197781.r481886

Is the topic of the review discussed comprehensively in the context of the current literature?

Yes
Are all factual statements correct and adequately supported by citations?

Yes
Is the review written in accessible language?

Yes
Are the conclusions drawn appropriate in the context of the current research literature?

Yes

Competing Interests: No competing interests were disclosed.

Reviewer Expertise: Brain health; Brain aging; Neurodegeneration

I confirm that I have read this submission and believe that I have an appropriate level of expertise to confirm that it is of an acceptable scientific standard, however I have significant reservations, as outlined above.

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Author Response 18 Jun 2026

Zheng Liu, Guangxi Key Laboratory of Multimodal Biomarkers and Precision Diagnosis, College of Medical Laboratory and Biotechnology, Guilin Medical University, Guilin, 541004, China

18 Jun 2026

Author Response

The authors have addressed most of the comments that were raised by the previous reviewers. The paper is improved.
However, some minor issues still remain.

1. Introduction.
First paragraph. ... Continue reading The authors have addressed most of the comments that were raised by the previous reviewers. The paper is improved.
However, some minor issues still remain.

1. Introduction.
First paragraph. Say which is the most prevalent neurodegenerative disorder.
Second paragraph. Delete "the progressive degeneration of dopaminergic neurons within the substantia nigra pars compacta". Here it is only the clinical part of the disease that should be described.

Response:
We thank the reviewer for these helpful suggestions regarding the Introduction.
In the first paragraph, we have revised the opening sentence to clarify that Alzheimer's disease (AD) is the most prevalent neurodegenerative disorder worldwide, followed by Parkinson's disease (PD) as the second most common condition.
In the second paragraph, we have removed the pathological description "the progressive degeneration of dopaminergic neurons within the substantia nigra pars compacta" and now focus exclusively on the clinical presentation: "The clinical hallmark of PD comprises classic motor symptoms such as bradykinesia, resting tremor, and rigidity."

Third paragraph. Proteostasis is mentioned, but this concept is never developed.

Response:
We thank the reviewer for this observation. We have removed the term "proteostasis" from the third paragraph of the Introduction, as this concept was not developed elsewhere in the manuscript.

2. The diversity of PINK1 mutations.
In this paragraph you should mention Figure 1, which is never mentioned throughout the paper.

Response:
We have revised Section 2 to include a reference to Figure 1, which illustrates how pathogenic PINK1 variants disrupt the mitochondrial quality control pathway. The figure is now explicitly cited to support the discussion of loss-of-function mechanisms.

Section 4.3.
The authors should connect better neuroinflammation with PD pathogenesis.
Is the disruption of mitophagy that triggers neuroinflammation? or neuroinflammation is independent from mitophagy?

Response:
We thank the reviewer for this important question. We have added an explicit statement in Section 4.3 clarifying that neuroinflammation is not independent from mitophagy; instead, mitophagy disruption directly triggers neuroinflammation. The subsequent discussion on the cGAS-STING pathway, gut-brain axis evidence, and clinical IL-6 data in PINK1/PRKN patients has been retained, as these findings directly connect neuroinflammation to PD pathogenesis.

5. Conclusion. Last sentence. Add "can help to identify" after "A deeper understanding of these mechanisms.....
Spell out the acronyms such as TIM23, TRAP1, etc. etc.
Use PD instead of Parkinson's disease consistently throughout the text (as an example, see Conclusion).

Response:
We thank the reviewer for these helpful suggestions.
We have revised the final sentence of the Conclusion to add "can help to identify" as requested. All acronyms, including TIM23 (translocase of the inner membrane 23), TRAP1 (TNF receptor-associated protein 1), UBL (ubiquitin-like), LC3 (microtubule-associated protein 1 light chain 3), mtDNA (mitochondrial DNA), cGAS (cyclic GMP-AMP synthase), STING (stimulator of interferon genes), and USP30 (ubiquitin-specific protease 30), are now spelled out at their first appearance. Additionally, we have replaced all instances of "Parkinson's disease" with "PD" throughout the text, except for the first appearance in the Abstract where the full term is introduced.
The authors have addressed most of the comments that were raised by the previous reviewers. The paper is improved.
However, some minor issues still remain.

1. Introduction.
First paragraph. Say which is the most prevalent neurodegenerative disorder.
Second paragraph. Delete "the progressive degeneration of dopaminergic neurons within the substantia nigra pars compacta". Here it is only the clinical part of the disease that should be described.

Response:
We thank the reviewer for these helpful suggestions regarding the Introduction.
In the first paragraph, we have revised the opening sentence to clarify that Alzheimer's disease (AD) is the most prevalent neurodegenerative disorder worldwide, followed by Parkinson's disease (PD) as the second most common condition.
In the second paragraph, we have removed the pathological description "the progressive degeneration of dopaminergic neurons within the substantia nigra pars compacta" and now focus exclusively on the clinical presentation: "The clinical hallmark of PD comprises classic motor symptoms such as bradykinesia, resting tremor, and rigidity."

Third paragraph. Proteostasis is mentioned, but this concept is never developed.

Response:
We thank the reviewer for this observation. We have removed the term "proteostasis" from the third paragraph of the Introduction, as this concept was not developed elsewhere in the manuscript.

2. The diversity of PINK1 mutations.
In this paragraph you should mention Figure 1, which is never mentioned throughout the paper.

Response:
We have revised Section 2 to include a reference to Figure 1, which illustrates how pathogenic PINK1 variants disrupt the mitochondrial quality control pathway. The figure is now explicitly cited to support the discussion of loss-of-function mechanisms.

Section 4.3.
The authors should connect better neuroinflammation with PD pathogenesis.
Is the disruption of mitophagy that triggers neuroinflammation? or neuroinflammation is independent from mitophagy?

Response:
We thank the reviewer for this important question. We have added an explicit statement in Section 4.3 clarifying that neuroinflammation is not independent from mitophagy; instead, mitophagy disruption directly triggers neuroinflammation. The subsequent discussion on the cGAS-STING pathway, gut-brain axis evidence, and clinical IL-6 data in PINK1/PRKN patients has been retained, as these findings directly connect neuroinflammation to PD pathogenesis.

5. Conclusion. Last sentence. Add "can help to identify" after "A deeper understanding of these mechanisms.....
Spell out the acronyms such as TIM23, TRAP1, etc. etc.
Use PD instead of Parkinson's disease consistently throughout the text (as an example, see Conclusion).

Response:
We thank the reviewer for these helpful suggestions.
We have revised the final sentence of the Conclusion to add "can help to identify" as requested. All acronyms, including TIM23 (translocase of the inner membrane 23), TRAP1 (TNF receptor-associated protein 1), UBL (ubiquitin-like), LC3 (microtubule-associated protein 1 light chain 3), mtDNA (mitochondrial DNA), cGAS (cyclic GMP-AMP synthase), STING (stimulator of interferon genes), and USP30 (ubiquitin-specific protease 30), are now spelled out at their first appearance. Additionally, we have replaced all instances of "Parkinson's disease" with "PD" throughout the text, except for the first appearance in the Abstract where the full term is introduced.
Competing Interests: No. Close
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COMMENTS ON THIS REPORT

Author Response 18 Jun 2026

Zheng Liu, Guangxi Key Laboratory of Multimodal Biomarkers and Precision Diagnosis, College of Medical Laboratory and Biotechnology, Guilin Medical University, Guilin, 541004, China

18 Jun 2026

Author Response

The authors have addressed most of the comments that were raised by the previous reviewers. The paper is improved.
However, some minor issues still remain.

1. Introduction.
First paragraph. ... Continue reading The authors have addressed most of the comments that were raised by the previous reviewers. The paper is improved.
However, some minor issues still remain.

1. Introduction.
First paragraph. Say which is the most prevalent neurodegenerative disorder.
Second paragraph. Delete "the progressive degeneration of dopaminergic neurons within the substantia nigra pars compacta". Here it is only the clinical part of the disease that should be described.

Response:
We thank the reviewer for these helpful suggestions regarding the Introduction.
In the first paragraph, we have revised the opening sentence to clarify that Alzheimer's disease (AD) is the most prevalent neurodegenerative disorder worldwide, followed by Parkinson's disease (PD) as the second most common condition.
In the second paragraph, we have removed the pathological description "the progressive degeneration of dopaminergic neurons within the substantia nigra pars compacta" and now focus exclusively on the clinical presentation: "The clinical hallmark of PD comprises classic motor symptoms such as bradykinesia, resting tremor, and rigidity."

Third paragraph. Proteostasis is mentioned, but this concept is never developed.

Response:
We thank the reviewer for this observation. We have removed the term "proteostasis" from the third paragraph of the Introduction, as this concept was not developed elsewhere in the manuscript.

2. The diversity of PINK1 mutations.
In this paragraph you should mention Figure 1, which is never mentioned throughout the paper.

Response:
We have revised Section 2 to include a reference to Figure 1, which illustrates how pathogenic PINK1 variants disrupt the mitochondrial quality control pathway. The figure is now explicitly cited to support the discussion of loss-of-function mechanisms.

Section 4.3.
The authors should connect better neuroinflammation with PD pathogenesis.
Is the disruption of mitophagy that triggers neuroinflammation? or neuroinflammation is independent from mitophagy?

Response:
We thank the reviewer for this important question. We have added an explicit statement in Section 4.3 clarifying that neuroinflammation is not independent from mitophagy; instead, mitophagy disruption directly triggers neuroinflammation. The subsequent discussion on the cGAS-STING pathway, gut-brain axis evidence, and clinical IL-6 data in PINK1/PRKN patients has been retained, as these findings directly connect neuroinflammation to PD pathogenesis.

5. Conclusion. Last sentence. Add "can help to identify" after "A deeper understanding of these mechanisms.....
Spell out the acronyms such as TIM23, TRAP1, etc. etc.
Use PD instead of Parkinson's disease consistently throughout the text (as an example, see Conclusion).

Response:
We thank the reviewer for these helpful suggestions.
We have revised the final sentence of the Conclusion to add "can help to identify" as requested. All acronyms, including TIM23 (translocase of the inner membrane 23), TRAP1 (TNF receptor-associated protein 1), UBL (ubiquitin-like), LC3 (microtubule-associated protein 1 light chain 3), mtDNA (mitochondrial DNA), cGAS (cyclic GMP-AMP synthase), STING (stimulator of interferon genes), and USP30 (ubiquitin-specific protease 30), are now spelled out at their first appearance. Additionally, we have replaced all instances of "Parkinson's disease" with "PD" throughout the text, except for the first appearance in the Abstract where the full term is introduced.
The authors have addressed most of the comments that were raised by the previous reviewers. The paper is improved.
However, some minor issues still remain.

1. Introduction.
First paragraph. Say which is the most prevalent neurodegenerative disorder.
Second paragraph. Delete "the progressive degeneration of dopaminergic neurons within the substantia nigra pars compacta". Here it is only the clinical part of the disease that should be described.

Response:
We thank the reviewer for these helpful suggestions regarding the Introduction.
In the first paragraph, we have revised the opening sentence to clarify that Alzheimer's disease (AD) is the most prevalent neurodegenerative disorder worldwide, followed by Parkinson's disease (PD) as the second most common condition.
In the second paragraph, we have removed the pathological description "the progressive degeneration of dopaminergic neurons within the substantia nigra pars compacta" and now focus exclusively on the clinical presentation: "The clinical hallmark of PD comprises classic motor symptoms such as bradykinesia, resting tremor, and rigidity."

Third paragraph. Proteostasis is mentioned, but this concept is never developed.

Response:
We thank the reviewer for this observation. We have removed the term "proteostasis" from the third paragraph of the Introduction, as this concept was not developed elsewhere in the manuscript.

2. The diversity of PINK1 mutations.
In this paragraph you should mention Figure 1, which is never mentioned throughout the paper.

Response:
We have revised Section 2 to include a reference to Figure 1, which illustrates how pathogenic PINK1 variants disrupt the mitochondrial quality control pathway. The figure is now explicitly cited to support the discussion of loss-of-function mechanisms.

Section 4.3.
The authors should connect better neuroinflammation with PD pathogenesis.
Is the disruption of mitophagy that triggers neuroinflammation? or neuroinflammation is independent from mitophagy?

Response:
We thank the reviewer for this important question. We have added an explicit statement in Section 4.3 clarifying that neuroinflammation is not independent from mitophagy; instead, mitophagy disruption directly triggers neuroinflammation. The subsequent discussion on the cGAS-STING pathway, gut-brain axis evidence, and clinical IL-6 data in PINK1/PRKN patients has been retained, as these findings directly connect neuroinflammation to PD pathogenesis.

5. Conclusion. Last sentence. Add "can help to identify" after "A deeper understanding of these mechanisms.....
Spell out the acronyms such as TIM23, TRAP1, etc. etc.
Use PD instead of Parkinson's disease consistently throughout the text (as an example, see Conclusion).

Response:
We thank the reviewer for these helpful suggestions.
We have revised the final sentence of the Conclusion to add "can help to identify" as requested. All acronyms, including TIM23 (translocase of the inner membrane 23), TRAP1 (TNF receptor-associated protein 1), UBL (ubiquitin-like), LC3 (microtubule-associated protein 1 light chain 3), mtDNA (mitochondrial DNA), cGAS (cyclic GMP-AMP synthase), STING (stimulator of interferon genes), and USP30 (ubiquitin-specific protease 30), are now spelled out at their first appearance. Additionally, we have replaced all instances of "Parkinson's disease" with "PD" throughout the text, except for the first appearance in the Abstract where the full term is introduced.
Competing Interests: No. Close
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Version 1

VERSION 1

PUBLISHED 20 Oct 2025

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Reviewer Report 30 Dec 2025

Ryan L Davis, University of Sydney, Sydney, Sydney, Australia

Not Approved

https://doi.org/10.5256/f1000research.187509.r425648

Mechanisms Associated with PINK1 Mutations in Parkinson's Disease

ABSTRACT
Gene names should be in italics

PINK1 and PTEN induced kinase 1 are the HGNC approved symbol and name – perhaps include the stable ID; HGNC:14581

“Central to its pathogenesis is the PINK1 gene…” is a broad overgeneralisation that makes it seem like PINK1 is the only cause of PD and not more specific to monogenic early-onset familial PD.

INTRODUCTION

Parkinson’s disease is defined as (PD) in the first line, but the abbreviation is not consistently used thereafter

There is a lot of information in the first paragraph that is not appropriately attributed to the original publications. Even a WHO report is mentioned but not referenced. Only the last sentence has an appropriate citation.

“Within four years of diagnosis, there is a rapid and nearly complete loss of dopaminergic markers
in the dorsal striatum” neglects the fact that there is a long pro-drome with progressive neurodegeneration. It also reflects the older onset progression of PD and not the early onset monogenic form that is relevant to PINK1. Might need to compare and contrast late vs early onset and idiopathic vs familial.

Please check whether ‘variant’ is more appropriate than ‘mutation’

Not sure how appropriate it is to reference a review for core research results. Reference the original citations where possible.

Some citations are quite old. Suggest searching for more contemporary research evidencing the claims made.

“PINK1 (PTEN-induced putative kinase 1) mutations represent the second most common cause of autosomal recessive early-onset Parkinson’s disease (EOPD), following Parkin mutations” suggests you are talking about the genes, and therefore PINK1 should be in italics and Parkin should be PRKN.

2. DIVERSITY OF PINK1 MUTATIONS
“Mutations in the PINK1 gene are strongly linked to PD” is suggestive that this is not definitive but rather remains controversial, which certainly isn’t the case. It would seem that this sentence is perfunctory.

First paragraph has no references to support the information presented.

Perhaps the second paragraph could be contextualised with the current extent of PINK1 variants and then perhaps that might help address the next comment.

If the variants have been known for over 20 years how do they “…offers valuable guidance for the development of future therapeutic interventions.”?

I would almost introduce normal PINK1 activity and physiology before talking about variants and how the dysfunction of the molecule underpins pathogenesis. As it stands, we’re learning about variants before really understanding the normal function and mechanisms of PINK1 activitiy.

3. PINK1 AND THE PATHOGENESIS OF PD

3.1 PINK1 MUTATIONS AND MITOCHONDRIAL PHOSPHORYLATION

The section title suggests PINK1 phosphorylates mitochondria. Instead, a more accurate section title might be PINK1 mutations and target protein phosphorylation

Figure legends should explain a figure as if it were standalone. Figure 1 only has a figure legend title and no supporting description of what is depicted. From author instructions for Reviews: “Titles and legends: Each figure or table should have a concise title of no more than 15 words. A legend for each figure and table should also be provided that briefly describes the key points and explains any symbols and abbreviations used. The legend should be sufficiently detailed so that the figure or table can stand alone from the main text.” This is currently not the case for Figure 1.

3.2 PINK1 MUTATIONS AND ABNORMAL MITOPHAGY PATHWAYS

Parkin is introduced here as if it is the first time it is introduced with its function etc. yet it appears in all sections above

While p62 was originally the best characterised autophagy receptor for Parkin-mediated mitophagy, there are several others that have been identified as being more prominent, including optineurin and NDP52. While NBR1 and TAX1BP1 are less prominent like p62.

OVERALL

Overall I found this short review to provide limited insight into the role of PINK1 in Parkinson’s disease with often outdated or incomplete supporting literature. PINK1 and Parkin have considerable influence outside of mitophagy, for instance PINK1 and Parkin were shown to be central to innate immunity in a knockout model where PD was induced by intestinal infection.

Additionally, mitochondrial dysfunction can be the cause or corollary in PD and while this review takes the simplistic and repeated view of PINK1 and Parkin centrality to mitophagy, it is a limited view and negates the peripheral complexities and multifaceted nature of PD pathogenesis.

As such, this review does nothing more than to reiterate information that have been presented ad nauseum without opinion or insight into the potential for therapeutic treatment that has thus far failed and remains an endeavour for the entire field.

While the review is generally well written it lacks originality in insight and opinion that would drive the field in a particular direction, as a good review should do.

As a result, I think this review is severely lacking and adds little to the literature that hasn’t already been presented numerous times previously.

Is the topic of the review discussed comprehensively in the context of the current literature?

No
Are all factual statements correct and adequately supported by citations?

Partly
Is the review written in accessible language?

Yes
Are the conclusions drawn appropriate in the context of the current research literature?

No

Competing Interests: No competing interests were disclosed.

Reviewer Expertise: Molecular Pathology, neurogenomics, Parkinson's Disease, Mitochondrial Disease

I confirm that I have read this submission and believe that I have an appropriate level of expertise to state that I do not consider it to be of an acceptable scientific standard, for reasons outlined above.

CITE

Report a concern

Author Response 22 Apr 2026

Zheng Liu, Guangxi Key Laboratory of Multimodal Biomarkers and Precision Diagnosis, College of Medical Laboratory and Biotechnology, Guilin Medical University, Guilin, 541004, China

22 Apr 2026

Author Response

Mechanisms Associated with PINK1 Mutations in Parkinson's Disease
ABSTRACT
Gene names should be in italics
PINK1 and PTEN induced kinase 1 are the HGNC approved symbol and name – perhaps ... Continue reading Mechanisms Associated with PINK1 Mutations in Parkinson's Disease
ABSTRACT
Gene names should be in italics
PINK1 and PTEN induced kinase 1 are the HGNC approved symbol and name – perhaps include the stable ID; HGNC:14581
Respond: In accordance with the reviewer's suggestion, we have italicized all gene names (e.g., PINK1) throughout the manuscript to distinguish them from their protein products. Additionally, we have included the HGNC approved symbol, full name, and the stable ID (HGNC:14581) at the first mention of the gene in the Introduction.

“Central to its pathogenesis is the PINK1 gene…” is a broad overgeneralisation that makes it seem like PINK1 is the only cause of PD and not more specific to monogenic early-onset familial PD.
Respond: We agree with the reviewer that the original statement was too broad. We have revised the text, “While most cases are sporadic, loss-of-function variants in the PINK1 gene are a primary cause of autosomal recessive early-onset PD.”. We have also clarified that studying PINK1 provides a critical window into mitochondrial dysfunction, which is a shared feature in both familial and sporadic PD.

INTRODUCTION
Parkinson’s disease is defined as (PD) in the first line, but the abbreviation is not consistently used thereafter
Respond: We appreciate the reviewer's attention to detail. We have corrected this throughout the manuscript. Following the initial definition in the first sentence of the Introduction, the abbreviation "PD" is now used consistently in place of the full term.

There is a lot of information in the first paragraph that is not appropriately attributed to the original publications. Even a WHO report is mentioned but not referenced. Only the last sentence has an appropriate citation.
Respond: We apologize for the insufficient citations in the original draft. We have now added the appropriate references for the epidemiological data and specifically cited the World Health Organization (WHO) report on Parkinson’s disease as requested.

“Within four years of diagnosis, there is a rapid and nearly complete loss of dopaminergic markers
in the dorsal striatum” neglects the fact that there is a long pro-drome with progressive neurodegeneration. It also reflects the older onset progression of PD and not the early onset monogenic form that is relevant to PINK1. Might need to compare and contrast late vs early onset and idiopathic vs familial.
Respond: We appreciate this insightful comment. In the revised Introduction (Paragraph 2), we have addressed this by:
1. Acknowledging the prolonged prodromal phase that precedes motor symptoms.
2. Explicitly distinguishing the clinical phenotype of PINK1-linked PD from idiopathic cases. We now clarify that PINK1 variants are associated with early-onset Parkinsonism (often before age 45) and a sustained response to levodopa, contrasting this with the older-onset progression of sporadic PD as suggested.

Please check whether ‘variant’ is more appropriate than ‘mutation’
Respond: We completely agree with the reviewer. In accordance with current genetic nomenclature guidelines, we have globally replaced the term "mutation" with "variant" throughout the manuscript to describe pathogenic genetic alterations.

Not sure how appropriate it is to reference a review for core research results. Reference the original citations where possible. Some citations are quite old. Suggest searching for more contemporary research evidencing the claims made.
Respond: We appreciate this valid critique. We have comprehensively audited our reference list. We have removed over-reliance on older review articles and replaced them with highly relevant, contemporary primary research articles.

“PINK1 (PTEN-induced putative kinase 1) mutations represent the second most common cause of autosomal recessive early-onset Parkinson’s disease (EOPD), following Parkin mutations” suggests you are talking about the genes, and therefore PINK1 should be in italics and Parkin should be PRKN.
Respond: PINK1 has been in italics and Parkin has been changed to PRKN.

2. DIVERSITY OF PINK1 MUTATIONS
“Mutations in the PINK1 gene are strongly linked to PD” is suggestive that this is not definitive but rather remains controversial, which certainly isn’t the case. It would seem that this sentence is perfunctory.
Respond: the sentence has been rewrote.

First paragraph has no references to support the information presented.
Respond: the references has been added to the first paragraph.

Perhaps the second paragraph could be contextualised with the current extent of PINK1 variants and then perhaps that might help address the next comment.
Respond: Thank you for the suggestion. I agree that providing a broader context on the current landscape of PINK1 variants—such as the distinction between pathogenic mutations and benign variants, or the known mutation hotspots—would strengthen the paragraph. This additional detail would not only ground the discussion but also serve as a natural bridge to the subsequent point in the comment."

If the variants have been known for over 20 years how do they “…offers valuable guidance for the development of future therapeutic interventions.”?
Respond: We have extensively revised this section (now Section 3) to address the reviewer's concerns regarding clarity, referencing, and logical flow:
1. Definitive Language: We have removed the tentative phrasing and now explicitly state that pathogenic variants cause a loss of function, disrupting the neuroprotective response.
2. References Added: We have added the necessary citations to the opening paragraph to support the historical identification and structural clustering of these variants [Valente et al., 2004; Scholten et al., 2020].
3. Updated Context: We have updated the text to reflect the current landscape, noting that over 70 variants have been cataloged, and we have categorized them by mechanism (kinase inactivation vs. protein instability).
4. Removed Outdated Conclusion: We have removed the generic statement about "future therapeutic guidance." Instead, the section now concludes by summarizing the specific pathological outcome of these variants: the failure to sense mitochondrial depolarization and initiate mitophagy.

I would almost introduce normal PINK1 activity and physiology before talking about variants and how the dysfunction of the molecule underpins pathogenesis. As it stands, we’re learning about variants before really understanding the normal function and mechanisms of PINK1 activity.
Respond: We are grateful for this excellent suggestion. We agree that a solid understanding of the physiological function of PINK1 is a prerequisite for discussing its pathogenicity. In the revised manuscript, we have inserted a new section entitled "Section 2. Physiological Role and Regulation of PINK1" immediately following the Introduction. In this section, we now detail:
1. The canonical import of PINK1 into healthy mitochondria via the TOM/TIM complexes.
2. Its proteolytic processing by MPP and PARL.
3. Its rapid degradation via the N-end rule pathway.
4. Its function as a molecular sensor for mitochondrial membrane potential. This new section provides the necessary biological context before we introduce the pathogenic variants in the subsequent section (now Section 3).3. PINK1 AND THE PATHOGENESIS OF PD

3.1 PINK1 MUTATIONS AND MITOCHONDRIAL PHOSPHORYLATION
The section title suggests PINK1 phosphorylates mitochondria. Instead, a more accurate section title might be PINK1 mutations and target protein phosphorylation
Respond: We agree with the reviewer that the original title was imprecise. In the revised manuscript, we have renamed this section (now Section 4.1) to "PINK1 Variants Impair Phosphorylation of Downstream Substrates." This title more accurately reflects the mechanistic reality that PINK1 targets specific proteins—namely Parkin and Ubiquitin—rather than the mitochondrial organelle as a whole.

Figure legends should explain a figure as if it were standalone. Figure 1 only has a figure legend title and no supporting description of what is depicted. From author instructions for Reviews: “Titles and legends: Each figure or table should have a concise title of no more than 15 words. A legend for each figure and table should also be provided that briefly describes the key points and explains any symbols and abbreviations used. The legend should be sufficiently detailed so that the figure or table can stand alone from the main text.” This is currently not the case for Figure 1.
Respond: We apologize for this omission. We have provided a comprehensive, standalone legend for Figure 1 that thoroughly explains the depicted mechanisms, including basal turnover, mitophagy initiation (highlighting OPTN/NDP52), and the disease state. All abbreviations used in the figure are now explicitly defined in the legend. Additionally, we have ensured that Figure 1 is properly cited and integrated within the relevant mechanistic sections of the main text to guide the reader effectively.

3.2 PINK1 MUTATIONS AND ABNORMAL MITOPHAGY PATHWAYS
Parkin is introduced here as if it is the first time it is introduced with its function etc. yet it appears in all sections above
While p62 was originally the best characterised autophagy receptor for Parkin-mediated mitophagy, there are several others that have been identified as being more prominent, including optineurin and NDP52. While NBR1 and TAX1BP1 are less prominent like p62.
Respond: We are grateful to the reviewer for their careful reading and for pointing out this critical evolution in the field. We have made two major revisions to this section (now Section 4.2) to fully address these concerns:
1. Removal of redundant Parkin introduction: We apologize for the redundancy. With the addition of the new "Section 2. Physiological Role and Regulation of PINK1" earlier in the manuscript, Parkin's baseline function is now appropriately introduced upon its first mention. We have carefully revised Section 4.2 to remove the repetitive introduction of Parkin, ensuring a smoother logical flow.
2. Updating the mitophagy receptor consensus: We have significantly revised the text to reflect the current consensus on autophagy receptors. As the reviewer correctly pointed out, we now explicitly state that Optineurin (OPTN) and NDP52 are the primary receptors essential for mitophagy. We also briefly acknowledge that p62, NBR1, and TAX1BP1 play less prominent roles. Furthermore, we now detail how PINK1-mediated phosphorylation of ubiquitin serves as the specific signal to recruit OPTN and NDP52. Key citations have been added to support this updated, contemporary perspective.OVERALL

Overall I found this short review to provide limited insight into the role of PINK1 in Parkinson’s disease with often outdated or incomplete supporting literature. PINK1 and Parkin have considerable influence outside of mitophagy, for instance PINK1 and Parkin were shown to be central to innate immunity in a knockout model where PD was induced by intestinal infection.
Additionally, mitochondrial dysfunction can be the cause or corollary in PD and while this review takes the simplistic and repeated view of PINK1 and Parkin centrality to mitophagy, it is a limited view and negates the peripheral complexities and multifaceted nature of PD pathogenesis.
As such, this review does nothing more than to reiterate information that have been presented ad nauseum without opinion or insight into the potential for therapeutic treatment that has thus far failed and remains an endeavour for the entire field.
While the review is generally well written it lacks originality in insight and opinion that would drive the field in a particular direction, as a good review should do.
As a result, I think this review is severely lacking and adds little to the literature that hasn’t already been presented numerous times previously.
Respond: We are deeply grateful for this profound and constructive critique, which has fundamentally elevated the quality of our manuscript. We fully agree that our previous draft was too narrowly focused on canonical mitophagy and lacked forward-looking translational insights. To address this, we have made substantial additions:
1. Expansion Beyond Mitophagy (Innate Immunity & Gut-Brain Axis): We have added a completely new section (Section 4.3: Beyond Mitophagy: PINK1 and Neuroinflammation). As astutely suggested by the reviewer, we now extensively discuss the role of PINK1 as a critical immunological checkpoint. We specifically highlight the seminal Nature study demonstrating that intestinal infection triggers autoimmune mechanisms in Pink1-knockout mice via mitochondrial antigen presentation (Matheoud et al., 2019) , as well as the activation of the cGAS-STING pathway.
2. Translational Relevance and Therapeutic Insight: We have added another new section (Section 4.4: Therapeutic Implications) to provide the missing "insight and opinion" on drug development. We critically evaluate novel precision medicine strategies, specifically highlighting the amplification of kinase activity (via Kinetin) and the promising strategy of bypassing mitophagy blockades using USP30 inhibitors.
3. We believe these major revisions transform the manuscript from a mere descriptive summary into a critical, forward-looking review that offers a new framework for understanding PINK1 pathogenesis and developing targeted therapies.
Mechanisms Associated with PINK1 Mutations in Parkinson's Disease
ABSTRACT
Gene names should be in italics
PINK1 and PTEN induced kinase 1 are the HGNC approved symbol and name – perhaps include the stable ID; HGNC:14581
Respond: In accordance with the reviewer's suggestion, we have italicized all gene names (e.g., PINK1) throughout the manuscript to distinguish them from their protein products. Additionally, we have included the HGNC approved symbol, full name, and the stable ID (HGNC:14581) at the first mention of the gene in the Introduction.

“Central to its pathogenesis is the PINK1 gene…” is a broad overgeneralisation that makes it seem like PINK1 is the only cause of PD and not more specific to monogenic early-onset familial PD.
Respond: We agree with the reviewer that the original statement was too broad. We have revised the text, “While most cases are sporadic, loss-of-function variants in the PINK1 gene are a primary cause of autosomal recessive early-onset PD.”. We have also clarified that studying PINK1 provides a critical window into mitochondrial dysfunction, which is a shared feature in both familial and sporadic PD.

INTRODUCTION
Parkinson’s disease is defined as (PD) in the first line, but the abbreviation is not consistently used thereafter
Respond: We appreciate the reviewer's attention to detail. We have corrected this throughout the manuscript. Following the initial definition in the first sentence of the Introduction, the abbreviation "PD" is now used consistently in place of the full term.

There is a lot of information in the first paragraph that is not appropriately attributed to the original publications. Even a WHO report is mentioned but not referenced. Only the last sentence has an appropriate citation.
Respond: We apologize for the insufficient citations in the original draft. We have now added the appropriate references for the epidemiological data and specifically cited the World Health Organization (WHO) report on Parkinson’s disease as requested.

“Within four years of diagnosis, there is a rapid and nearly complete loss of dopaminergic markers
in the dorsal striatum” neglects the fact that there is a long pro-drome with progressive neurodegeneration. It also reflects the older onset progression of PD and not the early onset monogenic form that is relevant to PINK1. Might need to compare and contrast late vs early onset and idiopathic vs familial.
Respond: We appreciate this insightful comment. In the revised Introduction (Paragraph 2), we have addressed this by:
1. Acknowledging the prolonged prodromal phase that precedes motor symptoms.
2. Explicitly distinguishing the clinical phenotype of PINK1-linked PD from idiopathic cases. We now clarify that PINK1 variants are associated with early-onset Parkinsonism (often before age 45) and a sustained response to levodopa, contrasting this with the older-onset progression of sporadic PD as suggested.

Please check whether ‘variant’ is more appropriate than ‘mutation’
Respond: We completely agree with the reviewer. In accordance with current genetic nomenclature guidelines, we have globally replaced the term "mutation" with "variant" throughout the manuscript to describe pathogenic genetic alterations.

Not sure how appropriate it is to reference a review for core research results. Reference the original citations where possible. Some citations are quite old. Suggest searching for more contemporary research evidencing the claims made.
Respond: We appreciate this valid critique. We have comprehensively audited our reference list. We have removed over-reliance on older review articles and replaced them with highly relevant, contemporary primary research articles.

“PINK1 (PTEN-induced putative kinase 1) mutations represent the second most common cause of autosomal recessive early-onset Parkinson’s disease (EOPD), following Parkin mutations” suggests you are talking about the genes, and therefore PINK1 should be in italics and Parkin should be PRKN.
Respond: PINK1 has been in italics and Parkin has been changed to PRKN.

2. DIVERSITY OF PINK1 MUTATIONS
“Mutations in the PINK1 gene are strongly linked to PD” is suggestive that this is not definitive but rather remains controversial, which certainly isn’t the case. It would seem that this sentence is perfunctory.
Respond: the sentence has been rewrote.

First paragraph has no references to support the information presented.
Respond: the references has been added to the first paragraph.

Perhaps the second paragraph could be contextualised with the current extent of PINK1 variants and then perhaps that might help address the next comment.
Respond: Thank you for the suggestion. I agree that providing a broader context on the current landscape of PINK1 variants—such as the distinction between pathogenic mutations and benign variants, or the known mutation hotspots—would strengthen the paragraph. This additional detail would not only ground the discussion but also serve as a natural bridge to the subsequent point in the comment."

If the variants have been known for over 20 years how do they “…offers valuable guidance for the development of future therapeutic interventions.”?
Respond: We have extensively revised this section (now Section 3) to address the reviewer's concerns regarding clarity, referencing, and logical flow:
1. Definitive Language: We have removed the tentative phrasing and now explicitly state that pathogenic variants cause a loss of function, disrupting the neuroprotective response.
2. References Added: We have added the necessary citations to the opening paragraph to support the historical identification and structural clustering of these variants [Valente et al., 2004; Scholten et al., 2020].
3. Updated Context: We have updated the text to reflect the current landscape, noting that over 70 variants have been cataloged, and we have categorized them by mechanism (kinase inactivation vs. protein instability).
4. Removed Outdated Conclusion: We have removed the generic statement about "future therapeutic guidance." Instead, the section now concludes by summarizing the specific pathological outcome of these variants: the failure to sense mitochondrial depolarization and initiate mitophagy.

I would almost introduce normal PINK1 activity and physiology before talking about variants and how the dysfunction of the molecule underpins pathogenesis. As it stands, we’re learning about variants before really understanding the normal function and mechanisms of PINK1 activity.
Respond: We are grateful for this excellent suggestion. We agree that a solid understanding of the physiological function of PINK1 is a prerequisite for discussing its pathogenicity. In the revised manuscript, we have inserted a new section entitled "Section 2. Physiological Role and Regulation of PINK1" immediately following the Introduction. In this section, we now detail:
1. The canonical import of PINK1 into healthy mitochondria via the TOM/TIM complexes.
2. Its proteolytic processing by MPP and PARL.
3. Its rapid degradation via the N-end rule pathway.
4. Its function as a molecular sensor for mitochondrial membrane potential. This new section provides the necessary biological context before we introduce the pathogenic variants in the subsequent section (now Section 3).3. PINK1 AND THE PATHOGENESIS OF PD

3.1 PINK1 MUTATIONS AND MITOCHONDRIAL PHOSPHORYLATION
The section title suggests PINK1 phosphorylates mitochondria. Instead, a more accurate section title might be PINK1 mutations and target protein phosphorylation
Respond: We agree with the reviewer that the original title was imprecise. In the revised manuscript, we have renamed this section (now Section 4.1) to "PINK1 Variants Impair Phosphorylation of Downstream Substrates." This title more accurately reflects the mechanistic reality that PINK1 targets specific proteins—namely Parkin and Ubiquitin—rather than the mitochondrial organelle as a whole.

Figure legends should explain a figure as if it were standalone. Figure 1 only has a figure legend title and no supporting description of what is depicted. From author instructions for Reviews: “Titles and legends: Each figure or table should have a concise title of no more than 15 words. A legend for each figure and table should also be provided that briefly describes the key points and explains any symbols and abbreviations used. The legend should be sufficiently detailed so that the figure or table can stand alone from the main text.” This is currently not the case for Figure 1.
Respond: We apologize for this omission. We have provided a comprehensive, standalone legend for Figure 1 that thoroughly explains the depicted mechanisms, including basal turnover, mitophagy initiation (highlighting OPTN/NDP52), and the disease state. All abbreviations used in the figure are now explicitly defined in the legend. Additionally, we have ensured that Figure 1 is properly cited and integrated within the relevant mechanistic sections of the main text to guide the reader effectively.

3.2 PINK1 MUTATIONS AND ABNORMAL MITOPHAGY PATHWAYS
Parkin is introduced here as if it is the first time it is introduced with its function etc. yet it appears in all sections above
While p62 was originally the best characterised autophagy receptor for Parkin-mediated mitophagy, there are several others that have been identified as being more prominent, including optineurin and NDP52. While NBR1 and TAX1BP1 are less prominent like p62.
Respond: We are grateful to the reviewer for their careful reading and for pointing out this critical evolution in the field. We have made two major revisions to this section (now Section 4.2) to fully address these concerns:
1. Removal of redundant Parkin introduction: We apologize for the redundancy. With the addition of the new "Section 2. Physiological Role and Regulation of PINK1" earlier in the manuscript, Parkin's baseline function is now appropriately introduced upon its first mention. We have carefully revised Section 4.2 to remove the repetitive introduction of Parkin, ensuring a smoother logical flow.
2. Updating the mitophagy receptor consensus: We have significantly revised the text to reflect the current consensus on autophagy receptors. As the reviewer correctly pointed out, we now explicitly state that Optineurin (OPTN) and NDP52 are the primary receptors essential for mitophagy. We also briefly acknowledge that p62, NBR1, and TAX1BP1 play less prominent roles. Furthermore, we now detail how PINK1-mediated phosphorylation of ubiquitin serves as the specific signal to recruit OPTN and NDP52. Key citations have been added to support this updated, contemporary perspective.OVERALL

Overall I found this short review to provide limited insight into the role of PINK1 in Parkinson’s disease with often outdated or incomplete supporting literature. PINK1 and Parkin have considerable influence outside of mitophagy, for instance PINK1 and Parkin were shown to be central to innate immunity in a knockout model where PD was induced by intestinal infection.
Additionally, mitochondrial dysfunction can be the cause or corollary in PD and while this review takes the simplistic and repeated view of PINK1 and Parkin centrality to mitophagy, it is a limited view and negates the peripheral complexities and multifaceted nature of PD pathogenesis.
As such, this review does nothing more than to reiterate information that have been presented ad nauseum without opinion or insight into the potential for therapeutic treatment that has thus far failed and remains an endeavour for the entire field.
While the review is generally well written it lacks originality in insight and opinion that would drive the field in a particular direction, as a good review should do.
As a result, I think this review is severely lacking and adds little to the literature that hasn’t already been presented numerous times previously.
Respond: We are deeply grateful for this profound and constructive critique, which has fundamentally elevated the quality of our manuscript. We fully agree that our previous draft was too narrowly focused on canonical mitophagy and lacked forward-looking translational insights. To address this, we have made substantial additions:
1. Expansion Beyond Mitophagy (Innate Immunity & Gut-Brain Axis): We have added a completely new section (Section 4.3: Beyond Mitophagy: PINK1 and Neuroinflammation). As astutely suggested by the reviewer, we now extensively discuss the role of PINK1 as a critical immunological checkpoint. We specifically highlight the seminal Nature study demonstrating that intestinal infection triggers autoimmune mechanisms in Pink1-knockout mice via mitochondrial antigen presentation (Matheoud et al., 2019) , as well as the activation of the cGAS-STING pathway.
2. Translational Relevance and Therapeutic Insight: We have added another new section (Section 4.4: Therapeutic Implications) to provide the missing "insight and opinion" on drug development. We critically evaluate novel precision medicine strategies, specifically highlighting the amplification of kinase activity (via Kinetin) and the promising strategy of bypassing mitophagy blockades using USP30 inhibitors.
3. We believe these major revisions transform the manuscript from a mere descriptive summary into a critical, forward-looking review that offers a new framework for understanding PINK1 pathogenesis and developing targeted therapies.
Competing Interests: No competing interests were disclosed. Close
Report a concern
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COMMENTS ON THIS REPORT

Author Response 22 Apr 2026

Zheng Liu, Guangxi Key Laboratory of Multimodal Biomarkers and Precision Diagnosis, College of Medical Laboratory and Biotechnology, Guilin Medical University, Guilin, 541004, China

22 Apr 2026

Author Response

Mechanisms Associated with PINK1 Mutations in Parkinson's Disease
ABSTRACT
Gene names should be in italics
PINK1 and PTEN induced kinase 1 are the HGNC approved symbol and name – perhaps ... Continue reading Mechanisms Associated with PINK1 Mutations in Parkinson's Disease
ABSTRACT
Gene names should be in italics
PINK1 and PTEN induced kinase 1 are the HGNC approved symbol and name – perhaps include the stable ID; HGNC:14581
Respond: In accordance with the reviewer's suggestion, we have italicized all gene names (e.g., PINK1) throughout the manuscript to distinguish them from their protein products. Additionally, we have included the HGNC approved symbol, full name, and the stable ID (HGNC:14581) at the first mention of the gene in the Introduction.

“Central to its pathogenesis is the PINK1 gene…” is a broad overgeneralisation that makes it seem like PINK1 is the only cause of PD and not more specific to monogenic early-onset familial PD.
Respond: We agree with the reviewer that the original statement was too broad. We have revised the text, “While most cases are sporadic, loss-of-function variants in the PINK1 gene are a primary cause of autosomal recessive early-onset PD.”. We have also clarified that studying PINK1 provides a critical window into mitochondrial dysfunction, which is a shared feature in both familial and sporadic PD.

INTRODUCTION
Parkinson’s disease is defined as (PD) in the first line, but the abbreviation is not consistently used thereafter
Respond: We appreciate the reviewer's attention to detail. We have corrected this throughout the manuscript. Following the initial definition in the first sentence of the Introduction, the abbreviation "PD" is now used consistently in place of the full term.

There is a lot of information in the first paragraph that is not appropriately attributed to the original publications. Even a WHO report is mentioned but not referenced. Only the last sentence has an appropriate citation.
Respond: We apologize for the insufficient citations in the original draft. We have now added the appropriate references for the epidemiological data and specifically cited the World Health Organization (WHO) report on Parkinson’s disease as requested.

“Within four years of diagnosis, there is a rapid and nearly complete loss of dopaminergic markers
in the dorsal striatum” neglects the fact that there is a long pro-drome with progressive neurodegeneration. It also reflects the older onset progression of PD and not the early onset monogenic form that is relevant to PINK1. Might need to compare and contrast late vs early onset and idiopathic vs familial.
Respond: We appreciate this insightful comment. In the revised Introduction (Paragraph 2), we have addressed this by:
1. Acknowledging the prolonged prodromal phase that precedes motor symptoms.
2. Explicitly distinguishing the clinical phenotype of PINK1-linked PD from idiopathic cases. We now clarify that PINK1 variants are associated with early-onset Parkinsonism (often before age 45) and a sustained response to levodopa, contrasting this with the older-onset progression of sporadic PD as suggested.

Please check whether ‘variant’ is more appropriate than ‘mutation’
Respond: We completely agree with the reviewer. In accordance with current genetic nomenclature guidelines, we have globally replaced the term "mutation" with "variant" throughout the manuscript to describe pathogenic genetic alterations.

Not sure how appropriate it is to reference a review for core research results. Reference the original citations where possible. Some citations are quite old. Suggest searching for more contemporary research evidencing the claims made.
Respond: We appreciate this valid critique. We have comprehensively audited our reference list. We have removed over-reliance on older review articles and replaced them with highly relevant, contemporary primary research articles.

“PINK1 (PTEN-induced putative kinase 1) mutations represent the second most common cause of autosomal recessive early-onset Parkinson’s disease (EOPD), following Parkin mutations” suggests you are talking about the genes, and therefore PINK1 should be in italics and Parkin should be PRKN.
Respond: PINK1 has been in italics and Parkin has been changed to PRKN.

2. DIVERSITY OF PINK1 MUTATIONS
“Mutations in the PINK1 gene are strongly linked to PD” is suggestive that this is not definitive but rather remains controversial, which certainly isn’t the case. It would seem that this sentence is perfunctory.
Respond: the sentence has been rewrote.

First paragraph has no references to support the information presented.
Respond: the references has been added to the first paragraph.

Perhaps the second paragraph could be contextualised with the current extent of PINK1 variants and then perhaps that might help address the next comment.
Respond: Thank you for the suggestion. I agree that providing a broader context on the current landscape of PINK1 variants—such as the distinction between pathogenic mutations and benign variants, or the known mutation hotspots—would strengthen the paragraph. This additional detail would not only ground the discussion but also serve as a natural bridge to the subsequent point in the comment."

If the variants have been known for over 20 years how do they “…offers valuable guidance for the development of future therapeutic interventions.”?
Respond: We have extensively revised this section (now Section 3) to address the reviewer's concerns regarding clarity, referencing, and logical flow:
1. Definitive Language: We have removed the tentative phrasing and now explicitly state that pathogenic variants cause a loss of function, disrupting the neuroprotective response.
2. References Added: We have added the necessary citations to the opening paragraph to support the historical identification and structural clustering of these variants [Valente et al., 2004; Scholten et al., 2020].
3. Updated Context: We have updated the text to reflect the current landscape, noting that over 70 variants have been cataloged, and we have categorized them by mechanism (kinase inactivation vs. protein instability).
4. Removed Outdated Conclusion: We have removed the generic statement about "future therapeutic guidance." Instead, the section now concludes by summarizing the specific pathological outcome of these variants: the failure to sense mitochondrial depolarization and initiate mitophagy.

I would almost introduce normal PINK1 activity and physiology before talking about variants and how the dysfunction of the molecule underpins pathogenesis. As it stands, we’re learning about variants before really understanding the normal function and mechanisms of PINK1 activity.
Respond: We are grateful for this excellent suggestion. We agree that a solid understanding of the physiological function of PINK1 is a prerequisite for discussing its pathogenicity. In the revised manuscript, we have inserted a new section entitled "Section 2. Physiological Role and Regulation of PINK1" immediately following the Introduction. In this section, we now detail:
1. The canonical import of PINK1 into healthy mitochondria via the TOM/TIM complexes.
2. Its proteolytic processing by MPP and PARL.
3. Its rapid degradation via the N-end rule pathway.
4. Its function as a molecular sensor for mitochondrial membrane potential. This new section provides the necessary biological context before we introduce the pathogenic variants in the subsequent section (now Section 3).3. PINK1 AND THE PATHOGENESIS OF PD

3.1 PINK1 MUTATIONS AND MITOCHONDRIAL PHOSPHORYLATION
The section title suggests PINK1 phosphorylates mitochondria. Instead, a more accurate section title might be PINK1 mutations and target protein phosphorylation
Respond: We agree with the reviewer that the original title was imprecise. In the revised manuscript, we have renamed this section (now Section 4.1) to "PINK1 Variants Impair Phosphorylation of Downstream Substrates." This title more accurately reflects the mechanistic reality that PINK1 targets specific proteins—namely Parkin and Ubiquitin—rather than the mitochondrial organelle as a whole.

Figure legends should explain a figure as if it were standalone. Figure 1 only has a figure legend title and no supporting description of what is depicted. From author instructions for Reviews: “Titles and legends: Each figure or table should have a concise title of no more than 15 words. A legend for each figure and table should also be provided that briefly describes the key points and explains any symbols and abbreviations used. The legend should be sufficiently detailed so that the figure or table can stand alone from the main text.” This is currently not the case for Figure 1.
Respond: We apologize for this omission. We have provided a comprehensive, standalone legend for Figure 1 that thoroughly explains the depicted mechanisms, including basal turnover, mitophagy initiation (highlighting OPTN/NDP52), and the disease state. All abbreviations used in the figure are now explicitly defined in the legend. Additionally, we have ensured that Figure 1 is properly cited and integrated within the relevant mechanistic sections of the main text to guide the reader effectively.

3.2 PINK1 MUTATIONS AND ABNORMAL MITOPHAGY PATHWAYS
Parkin is introduced here as if it is the first time it is introduced with its function etc. yet it appears in all sections above
While p62 was originally the best characterised autophagy receptor for Parkin-mediated mitophagy, there are several others that have been identified as being more prominent, including optineurin and NDP52. While NBR1 and TAX1BP1 are less prominent like p62.
Respond: We are grateful to the reviewer for their careful reading and for pointing out this critical evolution in the field. We have made two major revisions to this section (now Section 4.2) to fully address these concerns:
1. Removal of redundant Parkin introduction: We apologize for the redundancy. With the addition of the new "Section 2. Physiological Role and Regulation of PINK1" earlier in the manuscript, Parkin's baseline function is now appropriately introduced upon its first mention. We have carefully revised Section 4.2 to remove the repetitive introduction of Parkin, ensuring a smoother logical flow.
2. Updating the mitophagy receptor consensus: We have significantly revised the text to reflect the current consensus on autophagy receptors. As the reviewer correctly pointed out, we now explicitly state that Optineurin (OPTN) and NDP52 are the primary receptors essential for mitophagy. We also briefly acknowledge that p62, NBR1, and TAX1BP1 play less prominent roles. Furthermore, we now detail how PINK1-mediated phosphorylation of ubiquitin serves as the specific signal to recruit OPTN and NDP52. Key citations have been added to support this updated, contemporary perspective.OVERALL

Overall I found this short review to provide limited insight into the role of PINK1 in Parkinson’s disease with often outdated or incomplete supporting literature. PINK1 and Parkin have considerable influence outside of mitophagy, for instance PINK1 and Parkin were shown to be central to innate immunity in a knockout model where PD was induced by intestinal infection.
Additionally, mitochondrial dysfunction can be the cause or corollary in PD and while this review takes the simplistic and repeated view of PINK1 and Parkin centrality to mitophagy, it is a limited view and negates the peripheral complexities and multifaceted nature of PD pathogenesis.
As such, this review does nothing more than to reiterate information that have been presented ad nauseum without opinion or insight into the potential for therapeutic treatment that has thus far failed and remains an endeavour for the entire field.
While the review is generally well written it lacks originality in insight and opinion that would drive the field in a particular direction, as a good review should do.
As a result, I think this review is severely lacking and adds little to the literature that hasn’t already been presented numerous times previously.
Respond: We are deeply grateful for this profound and constructive critique, which has fundamentally elevated the quality of our manuscript. We fully agree that our previous draft was too narrowly focused on canonical mitophagy and lacked forward-looking translational insights. To address this, we have made substantial additions:
1. Expansion Beyond Mitophagy (Innate Immunity & Gut-Brain Axis): We have added a completely new section (Section 4.3: Beyond Mitophagy: PINK1 and Neuroinflammation). As astutely suggested by the reviewer, we now extensively discuss the role of PINK1 as a critical immunological checkpoint. We specifically highlight the seminal Nature study demonstrating that intestinal infection triggers autoimmune mechanisms in Pink1-knockout mice via mitochondrial antigen presentation (Matheoud et al., 2019) , as well as the activation of the cGAS-STING pathway.
2. Translational Relevance and Therapeutic Insight: We have added another new section (Section 4.4: Therapeutic Implications) to provide the missing "insight and opinion" on drug development. We critically evaluate novel precision medicine strategies, specifically highlighting the amplification of kinase activity (via Kinetin) and the promising strategy of bypassing mitophagy blockades using USP30 inhibitors.
3. We believe these major revisions transform the manuscript from a mere descriptive summary into a critical, forward-looking review that offers a new framework for understanding PINK1 pathogenesis and developing targeted therapies.
Mechanisms Associated with PINK1 Mutations in Parkinson's Disease
ABSTRACT
Gene names should be in italics
PINK1 and PTEN induced kinase 1 are the HGNC approved symbol and name – perhaps include the stable ID; HGNC:14581
Respond: In accordance with the reviewer's suggestion, we have italicized all gene names (e.g., PINK1) throughout the manuscript to distinguish them from their protein products. Additionally, we have included the HGNC approved symbol, full name, and the stable ID (HGNC:14581) at the first mention of the gene in the Introduction.

“Central to its pathogenesis is the PINK1 gene…” is a broad overgeneralisation that makes it seem like PINK1 is the only cause of PD and not more specific to monogenic early-onset familial PD.
Respond: We agree with the reviewer that the original statement was too broad. We have revised the text, “While most cases are sporadic, loss-of-function variants in the PINK1 gene are a primary cause of autosomal recessive early-onset PD.”. We have also clarified that studying PINK1 provides a critical window into mitochondrial dysfunction, which is a shared feature in both familial and sporadic PD.

INTRODUCTION
Parkinson’s disease is defined as (PD) in the first line, but the abbreviation is not consistently used thereafter
Respond: We appreciate the reviewer's attention to detail. We have corrected this throughout the manuscript. Following the initial definition in the first sentence of the Introduction, the abbreviation "PD" is now used consistently in place of the full term.

There is a lot of information in the first paragraph that is not appropriately attributed to the original publications. Even a WHO report is mentioned but not referenced. Only the last sentence has an appropriate citation.
Respond: We apologize for the insufficient citations in the original draft. We have now added the appropriate references for the epidemiological data and specifically cited the World Health Organization (WHO) report on Parkinson’s disease as requested.

“Within four years of diagnosis, there is a rapid and nearly complete loss of dopaminergic markers
in the dorsal striatum” neglects the fact that there is a long pro-drome with progressive neurodegeneration. It also reflects the older onset progression of PD and not the early onset monogenic form that is relevant to PINK1. Might need to compare and contrast late vs early onset and idiopathic vs familial.
Respond: We appreciate this insightful comment. In the revised Introduction (Paragraph 2), we have addressed this by:
1. Acknowledging the prolonged prodromal phase that precedes motor symptoms.
2. Explicitly distinguishing the clinical phenotype of PINK1-linked PD from idiopathic cases. We now clarify that PINK1 variants are associated with early-onset Parkinsonism (often before age 45) and a sustained response to levodopa, contrasting this with the older-onset progression of sporadic PD as suggested.

Please check whether ‘variant’ is more appropriate than ‘mutation’
Respond: We completely agree with the reviewer. In accordance with current genetic nomenclature guidelines, we have globally replaced the term "mutation" with "variant" throughout the manuscript to describe pathogenic genetic alterations.

Not sure how appropriate it is to reference a review for core research results. Reference the original citations where possible. Some citations are quite old. Suggest searching for more contemporary research evidencing the claims made.
Respond: We appreciate this valid critique. We have comprehensively audited our reference list. We have removed over-reliance on older review articles and replaced them with highly relevant, contemporary primary research articles.

“PINK1 (PTEN-induced putative kinase 1) mutations represent the second most common cause of autosomal recessive early-onset Parkinson’s disease (EOPD), following Parkin mutations” suggests you are talking about the genes, and therefore PINK1 should be in italics and Parkin should be PRKN.
Respond: PINK1 has been in italics and Parkin has been changed to PRKN.

2. DIVERSITY OF PINK1 MUTATIONS
“Mutations in the PINK1 gene are strongly linked to PD” is suggestive that this is not definitive but rather remains controversial, which certainly isn’t the case. It would seem that this sentence is perfunctory.
Respond: the sentence has been rewrote.

First paragraph has no references to support the information presented.
Respond: the references has been added to the first paragraph.

Perhaps the second paragraph could be contextualised with the current extent of PINK1 variants and then perhaps that might help address the next comment.
Respond: Thank you for the suggestion. I agree that providing a broader context on the current landscape of PINK1 variants—such as the distinction between pathogenic mutations and benign variants, or the known mutation hotspots—would strengthen the paragraph. This additional detail would not only ground the discussion but also serve as a natural bridge to the subsequent point in the comment."

If the variants have been known for over 20 years how do they “…offers valuable guidance for the development of future therapeutic interventions.”?
Respond: We have extensively revised this section (now Section 3) to address the reviewer's concerns regarding clarity, referencing, and logical flow:
1. Definitive Language: We have removed the tentative phrasing and now explicitly state that pathogenic variants cause a loss of function, disrupting the neuroprotective response.
2. References Added: We have added the necessary citations to the opening paragraph to support the historical identification and structural clustering of these variants [Valente et al., 2004; Scholten et al., 2020].
3. Updated Context: We have updated the text to reflect the current landscape, noting that over 70 variants have been cataloged, and we have categorized them by mechanism (kinase inactivation vs. protein instability).
4. Removed Outdated Conclusion: We have removed the generic statement about "future therapeutic guidance." Instead, the section now concludes by summarizing the specific pathological outcome of these variants: the failure to sense mitochondrial depolarization and initiate mitophagy.

I would almost introduce normal PINK1 activity and physiology before talking about variants and how the dysfunction of the molecule underpins pathogenesis. As it stands, we’re learning about variants before really understanding the normal function and mechanisms of PINK1 activity.
Respond: We are grateful for this excellent suggestion. We agree that a solid understanding of the physiological function of PINK1 is a prerequisite for discussing its pathogenicity. In the revised manuscript, we have inserted a new section entitled "Section 2. Physiological Role and Regulation of PINK1" immediately following the Introduction. In this section, we now detail:
1. The canonical import of PINK1 into healthy mitochondria via the TOM/TIM complexes.
2. Its proteolytic processing by MPP and PARL.
3. Its rapid degradation via the N-end rule pathway.
4. Its function as a molecular sensor for mitochondrial membrane potential. This new section provides the necessary biological context before we introduce the pathogenic variants in the subsequent section (now Section 3).3. PINK1 AND THE PATHOGENESIS OF PD

3.1 PINK1 MUTATIONS AND MITOCHONDRIAL PHOSPHORYLATION
The section title suggests PINK1 phosphorylates mitochondria. Instead, a more accurate section title might be PINK1 mutations and target protein phosphorylation
Respond: We agree with the reviewer that the original title was imprecise. In the revised manuscript, we have renamed this section (now Section 4.1) to "PINK1 Variants Impair Phosphorylation of Downstream Substrates." This title more accurately reflects the mechanistic reality that PINK1 targets specific proteins—namely Parkin and Ubiquitin—rather than the mitochondrial organelle as a whole.

Figure legends should explain a figure as if it were standalone. Figure 1 only has a figure legend title and no supporting description of what is depicted. From author instructions for Reviews: “Titles and legends: Each figure or table should have a concise title of no more than 15 words. A legend for each figure and table should also be provided that briefly describes the key points and explains any symbols and abbreviations used. The legend should be sufficiently detailed so that the figure or table can stand alone from the main text.” This is currently not the case for Figure 1.
Respond: We apologize for this omission. We have provided a comprehensive, standalone legend for Figure 1 that thoroughly explains the depicted mechanisms, including basal turnover, mitophagy initiation (highlighting OPTN/NDP52), and the disease state. All abbreviations used in the figure are now explicitly defined in the legend. Additionally, we have ensured that Figure 1 is properly cited and integrated within the relevant mechanistic sections of the main text to guide the reader effectively.

3.2 PINK1 MUTATIONS AND ABNORMAL MITOPHAGY PATHWAYS
Parkin is introduced here as if it is the first time it is introduced with its function etc. yet it appears in all sections above
While p62 was originally the best characterised autophagy receptor for Parkin-mediated mitophagy, there are several others that have been identified as being more prominent, including optineurin and NDP52. While NBR1 and TAX1BP1 are less prominent like p62.
Respond: We are grateful to the reviewer for their careful reading and for pointing out this critical evolution in the field. We have made two major revisions to this section (now Section 4.2) to fully address these concerns:
1. Removal of redundant Parkin introduction: We apologize for the redundancy. With the addition of the new "Section 2. Physiological Role and Regulation of PINK1" earlier in the manuscript, Parkin's baseline function is now appropriately introduced upon its first mention. We have carefully revised Section 4.2 to remove the repetitive introduction of Parkin, ensuring a smoother logical flow.
2. Updating the mitophagy receptor consensus: We have significantly revised the text to reflect the current consensus on autophagy receptors. As the reviewer correctly pointed out, we now explicitly state that Optineurin (OPTN) and NDP52 are the primary receptors essential for mitophagy. We also briefly acknowledge that p62, NBR1, and TAX1BP1 play less prominent roles. Furthermore, we now detail how PINK1-mediated phosphorylation of ubiquitin serves as the specific signal to recruit OPTN and NDP52. Key citations have been added to support this updated, contemporary perspective.OVERALL

Overall I found this short review to provide limited insight into the role of PINK1 in Parkinson’s disease with often outdated or incomplete supporting literature. PINK1 and Parkin have considerable influence outside of mitophagy, for instance PINK1 and Parkin were shown to be central to innate immunity in a knockout model where PD was induced by intestinal infection.
Additionally, mitochondrial dysfunction can be the cause or corollary in PD and while this review takes the simplistic and repeated view of PINK1 and Parkin centrality to mitophagy, it is a limited view and negates the peripheral complexities and multifaceted nature of PD pathogenesis.
As such, this review does nothing more than to reiterate information that have been presented ad nauseum without opinion or insight into the potential for therapeutic treatment that has thus far failed and remains an endeavour for the entire field.
While the review is generally well written it lacks originality in insight and opinion that would drive the field in a particular direction, as a good review should do.
As a result, I think this review is severely lacking and adds little to the literature that hasn’t already been presented numerous times previously.
Respond: We are deeply grateful for this profound and constructive critique, which has fundamentally elevated the quality of our manuscript. We fully agree that our previous draft was too narrowly focused on canonical mitophagy and lacked forward-looking translational insights. To address this, we have made substantial additions:
1. Expansion Beyond Mitophagy (Innate Immunity & Gut-Brain Axis): We have added a completely new section (Section 4.3: Beyond Mitophagy: PINK1 and Neuroinflammation). As astutely suggested by the reviewer, we now extensively discuss the role of PINK1 as a critical immunological checkpoint. We specifically highlight the seminal Nature study demonstrating that intestinal infection triggers autoimmune mechanisms in Pink1-knockout mice via mitochondrial antigen presentation (Matheoud et al., 2019) , as well as the activation of the cGAS-STING pathway.
2. Translational Relevance and Therapeutic Insight: We have added another new section (Section 4.4: Therapeutic Implications) to provide the missing "insight and opinion" on drug development. We critically evaluate novel precision medicine strategies, specifically highlighting the amplification of kinase activity (via Kinetin) and the promising strategy of bypassing mitophagy blockades using USP30 inhibitors.
3. We believe these major revisions transform the manuscript from a mere descriptive summary into a critical, forward-looking review that offers a new framework for understanding PINK1 pathogenesis and developing targeted therapies.
Competing Interests: No competing interests were disclosed. Close
Report a concern

Views

Reviewer Report 29 Dec 2025

Eman Ezzeldien Mohamed, Beni-Suef University, Beni-Suef, Egypt

Approved

https://doi.org/10.5256/f1000research.187509.r440954

Reviewer:
This manuscript addresses an important topic by reviewing the mechanisms linking PINK1 mutations to Parkinson’s disease. The review is generally well-referenced and provides informative coverage of mitochondrial dysfunction, autophagy, and oxidative stress.
1. The Introduction should more clearly define the scope of the review and highlight existing knowledge gaps. Several sections remain largely descriptive, and greater critical analysis of the literature is needed.
2. the Review should better explain the mechanistic reasons behind the reported pathological outcomes.
3. the clinical and translational relevance of PINK1 mutations could be more explicitly addressed. Improving integration between the figure and the main text would also enhance clarity.

Is the topic of the review discussed comprehensively in the context of the current literature?

Yes
Are all factual statements correct and adequately supported by citations?

Partly
Is the review written in accessible language?

Yes
Are the conclusions drawn appropriate in the context of the current research literature?

Yes

Competing Interests: No competing interests were disclosed.

Reviewer Expertise: physiology

I confirm that I have read this submission and believe that I have an appropriate level of expertise to confirm that it is of an acceptable scientific standard.

CITE

Report a concern

Author Response 22 Apr 2026

Zheng Liu, Guangxi Key Laboratory of Multimodal Biomarkers and Precision Diagnosis, College of Medical Laboratory and Biotechnology, Guilin Medical University, Guilin, 541004, China

22 Apr 2026

Author Response

This manuscript addresses an important topic by reviewing the mechanisms linking PINK1 mutations to Parkinson’s disease. The review is generally well-referenced and provides informative coverage of mitochondrial dysfunction, autophagy, and ... Continue reading This manuscript addresses an important topic by reviewing the mechanisms linking PINK1 mutations to Parkinson’s disease. The review is generally well-referenced and provides informative coverage of mitochondrial dysfunction, autophagy, and oxidative stress.

1. The Introduction should more clearly define the scope of the review and highlight existing knowledge gaps. Several sections remain largely descriptive, and greater critical analysis of the literature is needed.

Respond: We agree. We revised the Introduction's final paragraph to clearly define the review's scope and highlight knowledge gaps, specifically PINK1's non-mitophagic roles in innate immunity. We also cited seminal studies on the gut-brain axis and inflammation, such as Matheoud et al. (2019), to enhance our critical analysis.

2. the Review should better explain the mechanistic reasons behind the reported pathological outcomes.

Respond: Thank you for the suggestion. We significantly deepened the mechanistic discussions. In Section 3, we detail how specific variants fail to phosphorylate Ubiquitin/Parkin at Ser65. In Section 4.2, we explain how this failure blocks the recruitment of key autophagy receptors (OPTN and NDP52), leading to the accumulation of ROS-producing mitochondria that mechanically drives neurodegeneration.

3. the clinical and translational relevance of PINK1 mutations could be more explicitly addressed. Improving integration between the figure and the main text would also enhance clarity.

Respond: We appreciate these suggestions and made two major updates:
1.Translational Relevance: We added a new section (Section 4.4: Therapeutic Implications) exploring precision medicine strategies, highlighting neo-substrates (e.g., Kinetin) and USP30 inhibitors.
2. Figure Integration: We rewrote the legend for Figure 1 so it fully explains the mechanisms and stands alone. We also improved its integration by citing it at key mechanistic junctures (e.g., Sections 2 and 4.2) in the main text.
This manuscript addresses an important topic by reviewing the mechanisms linking PINK1 mutations to Parkinson’s disease. The review is generally well-referenced and provides informative coverage of mitochondrial dysfunction, autophagy, and oxidative stress.

1. The Introduction should more clearly define the scope of the review and highlight existing knowledge gaps. Several sections remain largely descriptive, and greater critical analysis of the literature is needed.

Respond: We agree. We revised the Introduction's final paragraph to clearly define the review's scope and highlight knowledge gaps, specifically PINK1's non-mitophagic roles in innate immunity. We also cited seminal studies on the gut-brain axis and inflammation, such as Matheoud et al. (2019), to enhance our critical analysis.

2. the Review should better explain the mechanistic reasons behind the reported pathological outcomes.

Respond: Thank you for the suggestion. We significantly deepened the mechanistic discussions. In Section 3, we detail how specific variants fail to phosphorylate Ubiquitin/Parkin at Ser65. In Section 4.2, we explain how this failure blocks the recruitment of key autophagy receptors (OPTN and NDP52), leading to the accumulation of ROS-producing mitochondria that mechanically drives neurodegeneration.

3. the clinical and translational relevance of PINK1 mutations could be more explicitly addressed. Improving integration between the figure and the main text would also enhance clarity.

Respond: We appreciate these suggestions and made two major updates:
1.Translational Relevance: We added a new section (Section 4.4: Therapeutic Implications) exploring precision medicine strategies, highlighting neo-substrates (e.g., Kinetin) and USP30 inhibitors.
2. Figure Integration: We rewrote the legend for Figure 1 so it fully explains the mechanisms and stands alone. We also improved its integration by citing it at key mechanistic junctures (e.g., Sections 2 and 4.2) in the main text.
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Author Response 22 Apr 2026

Zheng Liu, Guangxi Key Laboratory of Multimodal Biomarkers and Precision Diagnosis, College of Medical Laboratory and Biotechnology, Guilin Medical University, Guilin, 541004, China

22 Apr 2026

Author Response

This manuscript addresses an important topic by reviewing the mechanisms linking PINK1 mutations to Parkinson’s disease. The review is generally well-referenced and provides informative coverage of mitochondrial dysfunction, autophagy, and ... Continue reading This manuscript addresses an important topic by reviewing the mechanisms linking PINK1 mutations to Parkinson’s disease. The review is generally well-referenced and provides informative coverage of mitochondrial dysfunction, autophagy, and oxidative stress.

1. The Introduction should more clearly define the scope of the review and highlight existing knowledge gaps. Several sections remain largely descriptive, and greater critical analysis of the literature is needed.

Respond: We agree. We revised the Introduction's final paragraph to clearly define the review's scope and highlight knowledge gaps, specifically PINK1's non-mitophagic roles in innate immunity. We also cited seminal studies on the gut-brain axis and inflammation, such as Matheoud et al. (2019), to enhance our critical analysis.

2. the Review should better explain the mechanistic reasons behind the reported pathological outcomes.

Respond: Thank you for the suggestion. We significantly deepened the mechanistic discussions. In Section 3, we detail how specific variants fail to phosphorylate Ubiquitin/Parkin at Ser65. In Section 4.2, we explain how this failure blocks the recruitment of key autophagy receptors (OPTN and NDP52), leading to the accumulation of ROS-producing mitochondria that mechanically drives neurodegeneration.

3. the clinical and translational relevance of PINK1 mutations could be more explicitly addressed. Improving integration between the figure and the main text would also enhance clarity.

Respond: We appreciate these suggestions and made two major updates:
1.Translational Relevance: We added a new section (Section 4.4: Therapeutic Implications) exploring precision medicine strategies, highlighting neo-substrates (e.g., Kinetin) and USP30 inhibitors.
2. Figure Integration: We rewrote the legend for Figure 1 so it fully explains the mechanisms and stands alone. We also improved its integration by citing it at key mechanistic junctures (e.g., Sections 2 and 4.2) in the main text.
This manuscript addresses an important topic by reviewing the mechanisms linking PINK1 mutations to Parkinson’s disease. The review is generally well-referenced and provides informative coverage of mitochondrial dysfunction, autophagy, and oxidative stress.

1. The Introduction should more clearly define the scope of the review and highlight existing knowledge gaps. Several sections remain largely descriptive, and greater critical analysis of the literature is needed.

Respond: We agree. We revised the Introduction's final paragraph to clearly define the review's scope and highlight knowledge gaps, specifically PINK1's non-mitophagic roles in innate immunity. We also cited seminal studies on the gut-brain axis and inflammation, such as Matheoud et al. (2019), to enhance our critical analysis.

2. the Review should better explain the mechanistic reasons behind the reported pathological outcomes.

Respond: Thank you for the suggestion. We significantly deepened the mechanistic discussions. In Section 3, we detail how specific variants fail to phosphorylate Ubiquitin/Parkin at Ser65. In Section 4.2, we explain how this failure blocks the recruitment of key autophagy receptors (OPTN and NDP52), leading to the accumulation of ROS-producing mitochondria that mechanically drives neurodegeneration.

3. the clinical and translational relevance of PINK1 mutations could be more explicitly addressed. Improving integration between the figure and the main text would also enhance clarity.

Respond: We appreciate these suggestions and made two major updates:
1.Translational Relevance: We added a new section (Section 4.4: Therapeutic Implications) exploring precision medicine strategies, highlighting neo-substrates (e.g., Kinetin) and USP30 inhibitors.
2. Figure Integration: We rewrote the legend for Figure 1 so it fully explains the mechanisms and stands alone. We also improved its integration by citing it at key mechanistic junctures (e.g., Sections 2 and 4.2) in the main text.
Competing Interests: None. Close
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Version 3

VERSION 3 PUBLISHED 20 Oct 2025

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	1	2	3
Version 3 (revision) 18 Jun 26
Version 2 (revision) 22 Apr 26			read
Version 1 20 Oct 25	read	read

Eman Ezzeldien Mohamed, Beni-Suef University, Beni-Suef, Egypt
Ryan L Davis, University of Sydney, Sydney, Australia
DOMENICO PRATICO, Lewis Katz School of Medicine at Temple University, Philadelphia, USA

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Reviewer Report

9 Views

25 May 2026 | for Version 2

DOMENICO PRATICO, Department of Neural Sciences, Lewis Katz School of Medicine at Temple University, Philadelphia, Pennsylvania, USA

9 Views Cite this report Responses(1)

Approved With Reservations

Is the topic of the review discussed comprehensively in the context of the current literature?

Yes
Are all factual statements correct and adequately supported by citations?

Yes
Is the review written in accessible language?

Yes
Are the conclusions drawn appropriate in the context of the current research literature?

Yes

Competing Interests

No competing interests were disclosed.

Reviewer Expertise

Brain health; Brain aging; Neurodegeneration

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Responses (1)

Author Response

18 Jun 2026

Zheng Liu, Guangxi Key Laboratory of Multimodal Biomarkers and Precision Diagnosis, College of Medical Laboratory and Biotechnology, Guilin Medical University, Guilin, 541004, China

The authors have addressed most of the comments that were raised by the previous reviewers. The paper is improved.
However, some minor issues still remain.

1. Introduction.
First paragraph. Say which is the most prevalent neurodegenerative disorder.
Second paragraph. Delete "the progressive degeneration of dopaminergic neurons within the substantia nigra pars compacta". Here it is only the clinical part of the disease that should be described.

Response:
We thank the reviewer for these helpful suggestions regarding the Introduction.
In the first paragraph, we have revised the opening sentence to clarify that Alzheimer's disease (AD) is the most prevalent neurodegenerative disorder worldwide, followed by Parkinson's disease (PD) as the second most common condition.
In the second paragraph, we have removed the pathological description "the progressive degeneration of dopaminergic neurons within the substantia nigra pars compacta" and now focus exclusively on the clinical presentation: "The clinical hallmark of PD comprises classic motor symptoms such as bradykinesia, resting tremor, and rigidity."

Third paragraph. Proteostasis is mentioned, but this concept is never developed.

Response:
We thank the reviewer for this observation. We have removed the term "proteostasis" from the third paragraph of the Introduction, as this concept was not developed elsewhere in the manuscript.

2. The diversity of PINK1 mutations.
In this paragraph you should mention Figure 1, which is never mentioned throughout the paper.

Response:
We have revised Section 2 to include a reference to Figure 1, which illustrates how pathogenic PINK1 variants disrupt the mitochondrial quality control pathway. The figure is now explicitly cited to support the discussion of loss-of-function mechanisms.

Section 4.3.
The authors should connect better neuroinflammation with PD pathogenesis.
Is the disruption of mitophagy that triggers neuroinflammation? or neuroinflammation is independent from mitophagy?

Response:
We thank the reviewer for this important question. We have added an explicit statement in Section 4.3 clarifying that neuroinflammation is not independent from mitophagy; instead, mitophagy disruption directly triggers neuroinflammation. The subsequent discussion on the cGAS-STING pathway, gut-brain axis evidence, and clinical IL-6 data in PINK1/PRKN patients has been retained, as these findings directly connect neuroinflammation to PD pathogenesis.

5. Conclusion. Last sentence. Add "can help to identify" after "A deeper understanding of these mechanisms.....
Spell out the acronyms such as TIM23, TRAP1, etc. etc.
Use PD instead of Parkinson's disease consistently throughout the text (as an example, see Conclusion).

Response:
We thank the reviewer for these helpful suggestions.
We have revised the final sentence of the Conclusion to add "can help to identify" as requested. All acronyms, including TIM23 (translocase of the inner membrane 23), TRAP1 (TNF receptor-associated protein 1), UBL (ubiquitin-like), LC3 (microtubule-associated protein 1 light chain 3), mtDNA (mitochondrial DNA), cGAS (cyclic GMP-AMP synthase), STING (stimulator of interferon genes), and USP30 (ubiquitin-specific protease 30), are now spelled out at their first appearance. Additionally, we have replaced all instances of "Parkinson's disease" with "PD" throughout the text, except for the first appearance in the Abstract where the full term is introduced.

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Reviewer Report

24 Views

30 Dec 2025 | for Version 1

Ryan L Davis, University of Sydney, Sydney, Sydney, Australia

24 Views Cite this report Responses(1)

Not Approved

Is the topic of the review discussed comprehensively in the context of the current literature?

No
Are all factual statements correct and adequately supported by citations?

Partly
Is the review written in accessible language?

Yes
Are the conclusions drawn appropriate in the context of the current research literature?

No

Competing Interests

No competing interests were disclosed.

Reviewer Expertise

Molecular Pathology, neurogenomics, Parkinson's Disease, Mitochondrial Disease

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Author Response

22 Apr 2026

Zheng Liu, Guangxi Key Laboratory of Multimodal Biomarkers and Precision Diagnosis, College of Medical Laboratory and Biotechnology, Guilin Medical University, Guilin, 541004, China

Mechanisms Associated with PINK1 Mutations in Parkinson's Disease
ABSTRACT
Gene names should be in italics
PINK1 and PTEN induced kinase 1 are the HGNC approved symbol and name – perhaps include the stable ID; HGNC:14581
Respond: In accordance with the reviewer's suggestion, we have italicized all gene names (e.g., PINK1) throughout the manuscript to distinguish them from their protein products. Additionally, we have included the HGNC approved symbol, full name, and the stable ID (HGNC:14581) at the first mention of the gene in the Introduction.

“Central to its pathogenesis is the PINK1 gene…” is a broad overgeneralisation that makes it seem like PINK1 is the only cause of PD and not more specific to monogenic early-onset familial PD.
Respond: We agree with the reviewer that the original statement was too broad. We have revised the text, “While most cases are sporadic, loss-of-function variants in the PINK1 gene are a primary cause of autosomal recessive early-onset PD.”. We have also clarified that studying PINK1 provides a critical window into mitochondrial dysfunction, which is a shared feature in both familial and sporadic PD.

INTRODUCTION
Parkinson’s disease is defined as (PD) in the first line, but the abbreviation is not consistently used thereafter
Respond: We appreciate the reviewer's attention to detail. We have corrected this throughout the manuscript. Following the initial definition in the first sentence of the Introduction, the abbreviation "PD" is now used consistently in place of the full term.

There is a lot of information in the first paragraph that is not appropriately attributed to the original publications. Even a WHO report is mentioned but not referenced. Only the last sentence has an appropriate citation.
Respond: We apologize for the insufficient citations in the original draft. We have now added the appropriate references for the epidemiological data and specifically cited the World Health Organization (WHO) report on Parkinson’s disease as requested.

“Within four years of diagnosis, there is a rapid and nearly complete loss of dopaminergic markers
in the dorsal striatum” neglects the fact that there is a long pro-drome with progressive neurodegeneration. It also reflects the older onset progression of PD and not the early onset monogenic form that is relevant to PINK1. Might need to compare and contrast late vs early onset and idiopathic vs familial.
Respond: We appreciate this insightful comment. In the revised Introduction (Paragraph 2), we have addressed this by:
1. Acknowledging the prolonged prodromal phase that precedes motor symptoms.
2. Explicitly distinguishing the clinical phenotype of PINK1-linked PD from idiopathic cases. We now clarify that PINK1 variants are associated with early-onset Parkinsonism (often before age 45) and a sustained response to levodopa, contrasting this with the older-onset progression of sporadic PD as suggested.

Please check whether ‘variant’ is more appropriate than ‘mutation’
Respond: We completely agree with the reviewer. In accordance with current genetic nomenclature guidelines, we have globally replaced the term "mutation" with "variant" throughout the manuscript to describe pathogenic genetic alterations.

Not sure how appropriate it is to reference a review for core research results. Reference the original citations where possible. Some citations are quite old. Suggest searching for more contemporary research evidencing the claims made.
Respond: We appreciate this valid critique. We have comprehensively audited our reference list. We have removed over-reliance on older review articles and replaced them with highly relevant, contemporary primary research articles.

“PINK1 (PTEN-induced putative kinase 1) mutations represent the second most common cause of autosomal recessive early-onset Parkinson’s disease (EOPD), following Parkin mutations” suggests you are talking about the genes, and therefore PINK1 should be in italics and Parkin should be PRKN.
Respond: PINK1 has been in italics and Parkin has been changed to PRKN.

2. DIVERSITY OF PINK1 MUTATIONS
“Mutations in the PINK1 gene are strongly linked to PD” is suggestive that this is not definitive but rather remains controversial, which certainly isn’t the case. It would seem that this sentence is perfunctory.
Respond: the sentence has been rewrote.

First paragraph has no references to support the information presented.
Respond: the references has been added to the first paragraph.

Perhaps the second paragraph could be contextualised with the current extent of PINK1 variants and then perhaps that might help address the next comment.
Respond: Thank you for the suggestion. I agree that providing a broader context on the current landscape of PINK1 variants—such as the distinction between pathogenic mutations and benign variants, or the known mutation hotspots—would strengthen the paragraph. This additional detail would not only ground the discussion but also serve as a natural bridge to the subsequent point in the comment."

If the variants have been known for over 20 years how do they “…offers valuable guidance for the development of future therapeutic interventions.”?
Respond: We have extensively revised this section (now Section 3) to address the reviewer's concerns regarding clarity, referencing, and logical flow:
1. Definitive Language: We have removed the tentative phrasing and now explicitly state that pathogenic variants cause a loss of function, disrupting the neuroprotective response.
2. References Added: We have added the necessary citations to the opening paragraph to support the historical identification and structural clustering of these variants [Valente et al., 2004; Scholten et al., 2020].
3. Updated Context: We have updated the text to reflect the current landscape, noting that over 70 variants have been cataloged, and we have categorized them by mechanism (kinase inactivation vs. protein instability).
4. Removed Outdated Conclusion: We have removed the generic statement about "future therapeutic guidance." Instead, the section now concludes by summarizing the specific pathological outcome of these variants: the failure to sense mitochondrial depolarization and initiate mitophagy.

I would almost introduce normal PINK1 activity and physiology before talking about variants and how the dysfunction of the molecule underpins pathogenesis. As it stands, we’re learning about variants before really understanding the normal function and mechanisms of PINK1 activity.
Respond: We are grateful for this excellent suggestion. We agree that a solid understanding of the physiological function of PINK1 is a prerequisite for discussing its pathogenicity. In the revised manuscript, we have inserted a new section entitled "Section 2. Physiological Role and Regulation of PINK1" immediately following the Introduction. In this section, we now detail:
1. The canonical import of PINK1 into healthy mitochondria via the TOM/TIM complexes.
2. Its proteolytic processing by MPP and PARL.
3. Its rapid degradation via the N-end rule pathway.
4. Its function as a molecular sensor for mitochondrial membrane potential. This new section provides the necessary biological context before we introduce the pathogenic variants in the subsequent section (now Section 3).3. PINK1 AND THE PATHOGENESIS OF PD

3.1 PINK1 MUTATIONS AND MITOCHONDRIAL PHOSPHORYLATION
The section title suggests PINK1 phosphorylates mitochondria. Instead, a more accurate section title might be PINK1 mutations and target protein phosphorylation
Respond: We agree with the reviewer that the original title was imprecise. In the revised manuscript, we have renamed this section (now Section 4.1) to "PINK1 Variants Impair Phosphorylation of Downstream Substrates." This title more accurately reflects the mechanistic reality that PINK1 targets specific proteins—namely Parkin and Ubiquitin—rather than the mitochondrial organelle as a whole.

Figure legends should explain a figure as if it were standalone. Figure 1 only has a figure legend title and no supporting description of what is depicted. From author instructions for Reviews: “Titles and legends: Each figure or table should have a concise title of no more than 15 words. A legend for each figure and table should also be provided that briefly describes the key points and explains any symbols and abbreviations used. The legend should be sufficiently detailed so that the figure or table can stand alone from the main text.” This is currently not the case for Figure 1.
Respond: We apologize for this omission. We have provided a comprehensive, standalone legend for Figure 1 that thoroughly explains the depicted mechanisms, including basal turnover, mitophagy initiation (highlighting OPTN/NDP52), and the disease state. All abbreviations used in the figure are now explicitly defined in the legend. Additionally, we have ensured that Figure 1 is properly cited and integrated within the relevant mechanistic sections of the main text to guide the reader effectively.

3.2 PINK1 MUTATIONS AND ABNORMAL MITOPHAGY PATHWAYS
Parkin is introduced here as if it is the first time it is introduced with its function etc. yet it appears in all sections above
While p62 was originally the best characterised autophagy receptor for Parkin-mediated mitophagy, there are several others that have been identified as being more prominent, including optineurin and NDP52. While NBR1 and TAX1BP1 are less prominent like p62.
Respond: We are grateful to the reviewer for their careful reading and for pointing out this critical evolution in the field. We have made two major revisions to this section (now Section 4.2) to fully address these concerns:
1. Removal of redundant Parkin introduction: We apologize for the redundancy. With the addition of the new "Section 2. Physiological Role and Regulation of PINK1" earlier in the manuscript, Parkin's baseline function is now appropriately introduced upon its first mention. We have carefully revised Section 4.2 to remove the repetitive introduction of Parkin, ensuring a smoother logical flow.
2. Updating the mitophagy receptor consensus: We have significantly revised the text to reflect the current consensus on autophagy receptors. As the reviewer correctly pointed out, we now explicitly state that Optineurin (OPTN) and NDP52 are the primary receptors essential for mitophagy. We also briefly acknowledge that p62, NBR1, and TAX1BP1 play less prominent roles. Furthermore, we now detail how PINK1-mediated phosphorylation of ubiquitin serves as the specific signal to recruit OPTN and NDP52. Key citations have been added to support this updated, contemporary perspective.OVERALL

Overall I found this short review to provide limited insight into the role of PINK1 in Parkinson’s disease with often outdated or incomplete supporting literature. PINK1 and Parkin have considerable influence outside of mitophagy, for instance PINK1 and Parkin were shown to be central to innate immunity in a knockout model where PD was induced by intestinal infection.
Additionally, mitochondrial dysfunction can be the cause or corollary in PD and while this review takes the simplistic and repeated view of PINK1 and Parkin centrality to mitophagy, it is a limited view and negates the peripheral complexities and multifaceted nature of PD pathogenesis.
As such, this review does nothing more than to reiterate information that have been presented ad nauseum without opinion or insight into the potential for therapeutic treatment that has thus far failed and remains an endeavour for the entire field.
While the review is generally well written it lacks originality in insight and opinion that would drive the field in a particular direction, as a good review should do.
As a result, I think this review is severely lacking and adds little to the literature that hasn’t already been presented numerous times previously.
Respond: We are deeply grateful for this profound and constructive critique, which has fundamentally elevated the quality of our manuscript. We fully agree that our previous draft was too narrowly focused on canonical mitophagy and lacked forward-looking translational insights. To address this, we have made substantial additions:
1. Expansion Beyond Mitophagy (Innate Immunity & Gut-Brain Axis): We have added a completely new section (Section 4.3: Beyond Mitophagy: PINK1 and Neuroinflammation). As astutely suggested by the reviewer, we now extensively discuss the role of PINK1 as a critical immunological checkpoint. We specifically highlight the seminal Nature study demonstrating that intestinal infection triggers autoimmune mechanisms in Pink1-knockout mice via mitochondrial antigen presentation (Matheoud et al., 2019) , as well as the activation of the cGAS-STING pathway.
2. Translational Relevance and Therapeutic Insight: We have added another new section (Section 4.4: Therapeutic Implications) to provide the missing "insight and opinion" on drug development. We critically evaluate novel precision medicine strategies, specifically highlighting the amplification of kinase activity (via Kinetin) and the promising strategy of bypassing mitophagy blockades using USP30 inhibitors.
3. We believe these major revisions transform the manuscript from a mere descriptive summary into a critical, forward-looking review that offers a new framework for understanding PINK1 pathogenesis and developing targeted therapies.

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Competing Interests

No competing interests were disclosed.

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Reviewer Report

15 Views

29 Dec 2025 | for Version 1

Eman Ezzeldien Mohamed, Beni-Suef University, Beni-Suef, Egypt

15 Views Cite this report Responses(1)

Approved

Is the topic of the review discussed comprehensively in the context of the current literature?

Yes
Are all factual statements correct and adequately supported by citations?

Partly
Is the review written in accessible language?

Yes
Are the conclusions drawn appropriate in the context of the current research literature?

Yes

Competing Interests

No competing interests were disclosed.

Reviewer Expertise

physiology

I confirm that I have read this submission and believe that I have an appropriate level of expertise to confirm that it is of an acceptable scientific standard.

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Author Response

22 Apr 2026

Zheng Liu, Guangxi Key Laboratory of Multimodal Biomarkers and Precision Diagnosis, College of Medical Laboratory and Biotechnology, Guilin Medical University, Guilin, 541004, China

This manuscript addresses an important topic by reviewing the mechanisms linking PINK1 mutations to Parkinson’s disease. The review is generally well-referenced and provides informative coverage of mitochondrial dysfunction, autophagy, and oxidative stress.

1. The Introduction should more clearly define the scope of the review and highlight existing knowledge gaps. Several sections remain largely descriptive, and greater critical analysis of the literature is needed.

Respond: We agree. We revised the Introduction's final paragraph to clearly define the review's scope and highlight knowledge gaps, specifically PINK1's non-mitophagic roles in innate immunity. We also cited seminal studies on the gut-brain axis and inflammation, such as Matheoud et al. (2019), to enhance our critical analysis.

2. the Review should better explain the mechanistic reasons behind the reported pathological outcomes.

Respond: Thank you for the suggestion. We significantly deepened the mechanistic discussions. In Section 3, we detail how specific variants fail to phosphorylate Ubiquitin/Parkin at Ser65. In Section 4.2, we explain how this failure blocks the recruitment of key autophagy receptors (OPTN and NDP52), leading to the accumulation of ROS-producing mitochondria that mechanically drives neurodegeneration.

3. the clinical and translational relevance of PINK1 mutations could be more explicitly addressed. Improving integration between the figure and the main text would also enhance clarity.

Respond: We appreciate these suggestions and made two major updates:
1.Translational Relevance: We added a new section (Section 4.4: Therapeutic Implications) exploring precision medicine strategies, highlighting neo-substrates (e.g., Kinetin) and USP30 inhibitors.
2. Figure Integration: We rewrote the legend for Figure 1 so it fully explains the mechanisms and stands alone. We also improved its integration by citing it at key mechanistic junctures (e.g., Sections 2 and 4.2) in the main text.

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Competing Interests

None.

Alongside their report, reviewers assign a status to the article:

Approved - the paper is scientifically sound in its current form and only minor, if any, improvements are suggested

Approved with reservations - A number of small changes, sometimes more significant revisions are required to address specific details and improve the papers academic merit.

Not approved - fundamental flaws in the paper seriously undermine the findings and conclusions

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Mechanisms Associated with PINK1 Variants in Parkinson's Disease

Abstract

Abstract

Keywords

Revised Amendments from Version 1

1. Introduction

2. The diversity of PINK1 mutations

3. The diversity of PINK1 pathogenic variants

4. PINK1 and the pathogenesis of PD

4.1 PINK1 variants impair phosphorylation of downstream substrates

4.2 Disruption of mitophagy: The role of OPTN and NDP52

4.3 Beyond mitophagy: PINK1 and neuroinflammation

4.4 Therapeutic implications

5. Conclusions

Data availability

References

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