F1000ResearchF1000Research2046-1402F1000 Research LimitedLondon, UK10.12688/f1000research.170090.1ReviewArticlesMechanisms Associated with PINK1 Mutations in Parkinson's Disease
[version 1; peer review: 1 approved, 1 not approved]
DanHanliangInvestigationMethodologyWriting – Original Draft Preparationhttps://orcid.org/0000-0002-5507-2680123HuangXiaohuiInvestigationMethodologyWriting – Original Draft Preparation4LiuZhengConceptualizationWriting – Original Draft PreparationWriting – Review & Editinghttps://orcid.org/0000-0003-4158-6768a4WeiBingConceptualizationInvestigationWriting – Review & Editingb5MusaMaslindaConceptualizationSupervisionWriting – Original Draft PreparationWriting – Review & Editingc12
School of Biology, Faculty of Applied Sciences, Universiti Teknologi MARA, UiTM, Shah Alam Seksyen 2, 40450 Selangor, Malaysia
Centre for Chemical Synthesis and Polymer Technology, Institute of Science, Universiti Teknologi MARA, UiTM, Shah Alam Seksyen 2, 40450 Selangor, Malaysia
Nanxishan Hospital of Guangxi Zhuang Autonomous Region (The Second People's Hospital of Guangxi Zhuang Autonomous Region), Guilin, Guangxi 541002, China
Guangxi Key Laboratory of Multimodal Biomarkers and Precision Diagnosis, College of Medical Laboratory and Biotechnology, Guilin Medical University, Guilin, Guangxi, 541004, China
Guilin Medical University, Guangxi Key Laboratory of Tumor Immunology and Microenvironment Regulation, Department of Basic Medicine, Guilin, Guangxi 541004, Chinazliu1111@163.comweibing@glmu.edu.cnmaslinda64@uitm.edu.my
Parkinson’s disease (PD) is a widespread and progressively debilitating neurodegenerative disorder, with its global prevalence steadily increasing. Central to its pathogenesis is the PINK1 gene (PTEN-induced putative kinase 1), which plays a pivotal role in mitochondrial function and protecting cells from oxidative stress-induced apoptosis. This review explores the complex relationship between PINK1 mutations and PD, highlighting their involvement in key pathogenic mechanisms. It discusses how these mutations contribute to mitochondrial dysfunction, alterations in phosphorylation pathways, impaired autophagy, and heightened sensitivity to oxidative stress. These insights lay the groundwork for future research and therapeutic approaches, aiming to address the urgent need for effective PD interventions.
Parkinson's diseasePINK1genetic mutationmitochondrial phosphorylationautophagy pathwaysoxidative stressThe author(s) declared that no grants were involved in supporting this work.1. Introduction
Parkinson’s disease (PD) is a common, chronic, and progressive neurodegenerative disorder, second only to Alzheimer’s disease in prevalence. It affects both the central nervous system and peripheral organs, representing a growing health challenge as the global population ages. According to the
World Health Organization’s Parkinson’s Disease Report, more than 8.5 million people were living with PD in 2019, an 81% increase since 2000. During the same period, PD-related deaths doubled to 329,000. A meta-analysis of four North American populations revealed a strong age-related trend in prevalence: less than 1% among men and women aged 45–54 years, increasing to 4% in men and 2% in women aged 85 years and older.
1
The hallmark motor symptoms of PD include tremors, muscle rigidity, bradykinesia, postural instability, and reduced facial expression. The etiology of PD is multifactorial, likely involving interactions between genetic predisposition and environmental exposures. Established environmental risk factors include rural living, agricultural work, well-water consumption, and pesticide exposure.
2 Pathologically, PD is characterized by the degeneration of dopaminergic neurons in the substantia nigra. Within four years of diagnosis, there is a rapid and nearly complete loss of dopaminergic markers in the dorsal striatum, while the loss of melanin-containing neurons in the substantia nigra occurs with a relative delay.
3
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.
4 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.
5 Functionally, PINK1 plays a critical role in protecting cells from oxidative stress–induced apoptosis. Increasing research efforts are directed toward clarifying the biological functions of this serine/threonine kinase, with the goal of informing therapeutic development for PD.
6 The objective of this review is to examine the relationship between PINK1 mutations and Parkinson’s disease, and to elucidate the complex mechanisms involved, thereby providing valuable insights into potential therapeutic strategies.
2. The diversity of PINK1 mutations
Mutations in the PINK1 gene are strongly linked to PD. As a mitochondria-associated kinase, PINK1 plays a pivotal role in regulating mitochondrial biogenesis, quality control, and clearance. Loss or dysfunction of PINK1 disrupts these processes, leading to mitochondrial abnormalities characterized by altered morphology, reduced mitochondrial membrane potential (Δψm), and elevated reactive oxygen species (ROS) production, thereby promoting neurodegeneration.
Most pathogenic mutations in PINK1 occur within its kinase domain and include nonsense, missense, and deletion variants.
7 In 2004, Valente et al. first identified PINK1 mutations in three consanguineous families of the PARK6 pedigree, reporting two homozygous mutations within the kinase domain: a missense mutation (G309D) and a truncation mutation (W437X).
8 That same year, Hatano et al. identified six novel pathogenic variants (R246X, H271Q, E417G, L347P, and Q239X/R492X) in six unrelated PARK6 families.
9 Subsequent studies further revealed heterozygous mutations in sporadic early-onset PD, highlighting the role of PINK1 in both familial and sporadic disease forms.
10 Expanding research across diverse populations worldwide has identified additional homozygous and heterozygous mutations, many of which are predicted to impair or abolish kinase activity.
In vitro analyses confirm that mutations such as G309D, L437P, G386A, and G409V markedly reduce kinase function.
7,
11
Collectively, these studies provide comprehensive evidence of the close association between PINK1 mutations and PD, underscoring its critical role in early-onset familial and sporadic disease. A deeper understanding of the structural and functional consequences of these mutations has advanced our knowledge of mitochondrial regulation in PD pathogenesis and offers valuable guidance for the development of future therapeutic interventions.
3. PINK1 and the pathogenesis of PD3.1 PINK1 mutations and mitochondrial phosphorylation
Investigating the relationship between PINK1 mutations and phosphorylation pathways offers important insights into the molecular mechanisms underlying PD. Pridgeon et al. demonstrated that PINK1 kinase protects cells against oxidative stress–induced apoptosis by phosphorylating the mitochondrial chaperone TRAP1. However, PD-associated PINK1 mutations (G309D, L347P, and W437X) disrupt this protective mechanism, implicating them in disease pathogenesis.
12
Similarly, Plun-Favreau and colleagues identified PINK1’s interaction with the mitochondrial serine protease HtrA2/OMI.
13 Under physiological conditions, PINK1 activates the p38 pathway, which mediates HtrA2 phosphorylation and enhances its protease activity, thereby conferring resistance to cellular stress. In PD patients carrying PINK1 mutations such as C575R or Y431H, impaired HtrA2 phosphorylation diminishes this protective response, heightening vulnerability to mitochondrial stress.
13 Supporting evidence from Drosophila models confirmed that HtrA2/OMI functions downstream of PINK1 in a shared pathway, although independent of Parkin.
14,
15
Beyond HtrA2, Parkin itself has been identified as a direct substrate of PINK1. Di Sha et al. showed that PINK1 phosphorylates Parkin, thereby activating its E3 ligase activity, promoting K63-linked polyubiquitination, and enhancing NF-κB–mediated ubiquitin signaling. Notably, pathogenic PINK1 mutations (G309D and L347P) or kinase-inactive PINK1 abrogate this effect, abolishing Parkin phosphorylation and disrupting downstream signaling.
16
Further insights from Drosophila models highlight the essential role of PINK1 autophosphorylation at serine 346 in regulating the PINK1/Parkin pathway. Loss of this phosphorylation event impairs Parkin mitochondrial translocation and activation, ultimately exacerbating photoreceptor neurodegeneration. These findings emphasize the critical role of PINK1 autophosphorylation in mitochondrial quality control and neuronal survival.
17
Collectively, these studies demonstrate how PINK1 mutations compromise key phosphorylation pathways, thereby promoting mitochondrial dysfunction and neurodegeneration (
Figure 1). A deeper understanding of these processes not only clarifies PD pathogenesis but also highlights potential targets for therapeutic intervention.
Proposed mechanisms by which PINK1 dysfunction contributes to the pathogenesis of Parkinson’s disease.
3.2 PINK1 mutations and abnormal autophagy pathways
Mitophagy, the selective removal of damaged mitochondria via autophagosomes, is essential for maintaining mitochondrial quality and regulating mitochondrial number under varying cellular conditions.
In Parkinson’s disease, Parkin, an E3 ubiquitin ligase, plays a central role in mitochondrial quality control.
18 Loss of PINK1 function induces mitochondrial fragmentation and defective autophagy, a phenotype that can be rescued by PINK1 re-expression.
19 Under normal conditions, PINK1 undergoes voltage-dependent degradation by the mitochondrial inner membrane rhomboid protease PARL.
20,
21 However, when mitochondrial membrane potential collapses, PINK1 accumulates on the outer mitochondrial membrane of damaged mitochondria, serving as a signal for their clearance. This accumulated PINK1 recruits Parkin and activates it by phosphorylating ubiquitin at serine 65, establishing ubiquitin as a bona fide PINK1 substrate.
22 Phosphorylated ubiquitin allosterically promotes the release of UBCH7 ubiquitin, relieving Parkin’s autoinhibition and enhancing its E3 ligase activity.
18,
23 Once translocated to the mitochondrial surface, Parkin ubiquitinates multiple outer mitochondrial membrane (OMM) proteins, facilitating the recruitment of additional factors that initiate mitophagy.
24 In parallel, the ubiquitin-binding adaptor p62 (sequestosome 1) contributes by clustering ubiquitylated proteins through polymerization and recruiting them into autophagosomes via LC3 binding, thereby supporting constitutive basal autophagy.
25
Pathogenic PINK1 mutations disrupt this process by impairing both kinase activity and interaction with Parkin, thereby hindering the selective clearance of depolarized mitochondria and contributing to PD pathogenesis (
Figure 1). Geisler et al. demonstrated that PINK1 mutants W437X, Q126P, G309D, and L347P prevent Parkin translocation and block clearance of damaged mitochondria during mitophagy.
26 Interestingly, other studies suggest that these same variants, while impairing Parkin recruitment and kinase activity, may partially correct the aberrant autophagy induced by complete PINK1 deletion.
27
3.3 PINK1 mutations and oxidative stress
In 1983, Langston and colleagues reported that several individuals developed Parkinsonian symptoms following intravenous exposure to a banned compound, later identified as 1-methyl-4-phenyl-1,2,5,6-tetrahydropyridine (MPTP), suggesting its potential role as a PD trigger.
28 Structurally analogous to meperidine, MPTP itself is not directly toxic. After crossing the blood–brain barrier (BBB), it is metabolized by astrocytic enzymes into 1-methyl-4-phenyl-2,3-dihydropyridine, which is subsequently oxidized to the toxic metabolite 1-methyl-4-phenylpyridinium (MPP
+) within the central nervous system.
29,
30
Under normal conditions, electrons pass through mitochondrial respiratory chain complexes (I–IV) to generate ATP, with reactive oxygen species (ROS) produced as byproducts of oxygen metabolism.
31 While ROS are important for immune defense and cell signaling, their overproduction or impaired clearance leads to oxidative stress, which damages DNA, proteins, and lipids.
32 MPP
+ inhibits mitochondrial NADH dehydrogenase (complex I), resulting in excessive ROS generation and subsequent degeneration of dopaminergic neurons in the nigrostriatal pathway.
33
PINK1 plays a critical protective role in neuronal mitochondria (
Figure 1). Human neurons deficient in PINK1 display profound oxidative stress, widespread mitochondrial dysfunction, and abnormal morphology.
34 Deng et al. demonstrated that reduced PINK1 expression via siRNA decreased cell viability and increased susceptibility to MPP
+- and rotenone-induced cytotoxicity in SH-SY5Y cells, reinforcing PINK1’s role in dopaminergic neuron survival.
35 Further, Tang et al. identified novel heterozygous missense mutations—DJ-1 A39S and PINK1 P399L—in a Chinese family with early-onset PD. Their findings showed that DJ-1 and PINK1 form a protective complex against oxidative stress, while the disease-associated DJ-1 A39S and PINK1 P399L variants disrupt this interaction, thereby increasing vulnerability to neurotoxin-induced cell death.
36
4. Conclusions
In summary, this review highlights the intricate relationship between PINK1 mutations and Parkinson’s disease, emphasizing their effects on mitochondrial function, phosphorylation pathways, autophagy, and oxidative stress. By disrupting mitochondrial quality control, these mutations contribute to the cascade of events leading to neurodegeneration in PD. A deeper understanding of these pathogenic mechanisms not only provides a more comprehensive perspective on disease progression but also lays the groundwork for the development of targeted therapeutic strategies to address the challenges posed by Parkinson’s disease.
Data availability
No data are associated with this article.
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1663248610.1093/hmg/ddl10410.5256/f1000research.187509.r425648Reviewer response for version 1DavisRyan L1Referee
University of Sydney, Sydney, Sydney, Australia
Competing interests: No competing interests were disclosed.
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 review written in accessible language?
Yes
Are all factual statements correct and adequately supported by citations?
Partly
Are the conclusions drawn appropriate in the context of the current research literature?
No
Is the topic of the review discussed comprehensively in the context of the current literature?
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.
LiuZhengGuilin Medical University, China
Competing interests: No competing interests were disclosed.
1532026
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.
10.5256/f1000research.187509.r440954Reviewer response for version 1MohamedEman Ezzeldien1Referee
Beni-Suef University, Beni-Suef, Egypt
Competing interests: No competing interests were disclosed.
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 review written in accessible language?
Yes
Are all factual statements correct and adequately supported by citations?
Partly
Are the conclusions drawn appropriate in the context of the current research literature?
Yes
Is the topic of the review discussed comprehensively in the context of the current literature?
Yes
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.
LiuZhengGuilin Medical University, China
Competing interests: None.
1532026
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.