Loss of PINK1 Function Promotes Mitophagy through Effects on Oxidative Stress and Mitochondrial Fission
Open accessAbstract
Mitochondrial dysregulation is strongly implicated in Parkinson disease. Mutations in PTEN-induced kinase 1 (PINK1) are associated with familial parkinsonism and neuropsychiatric disorders. Although overexpressed PINK1 is neuroprotective, less is known about neuronal responses to loss of PINK1 function. We found that stable knockdown of PINK1 induced mitochondrial fragmentation and autophagy in SH-SY5Y cells, which was reversed by the reintroduction of an RNA interference (RNAi)-resistant plasmid for PINK1. Moreover, stable or transient overexpression of wild-type PINK1 increased mitochondrial interconnectivity and suppressed toxin-induced autophagy/mitophagy. Mitochondrial oxidant production played an essential role in triggering mitochondrial fragmentation and autophagy in PINK1 shRNA lines. Autophagy/mitophagy served a protective role in limiting cell death, and overexpressing Parkin further enhanced this protective mitophagic response. The dominant negative Drp1 mutant inhibited both fission and mitophagy in PINK1-deficient cells. Interestingly, RNAi knockdown of autophagy proteins Atg7 and LC3/Atg8 also decreased mitochondrial fragmentation without affecting oxidative stress, suggesting active involvement of autophagy in morphologic remodeling of mitochondria for clearance. To summarize, loss of PINK1 function elicits oxidative stress and mitochondrial turnover coordinated by the autophagic and fission/fusion machineries. Furthermore, PINK1 and Parkin may cooperate through different mechanisms to maintain mitochondrial homeostasis.
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The parameters used for mitochondrial morphology analysis have been previously validated in the literature.
“The utilization of these parameters has been previously validated in the literature using well-characterized mediators of mitochondrial fission and fusion.”
From Aging promotes an increase in mitochondrial fragmentation in astrocytes (2024) · cites this paper as Dagda et al., 2009
Complete loss of PINK1 can promote mitochondrial oxidant production and subsequent mitophagy.
“Interestingly, complete loss of PINK1 can promote mitochondrial oxidant production and subsequent mitophagy (107), possibly due to mitochondrial membrane damage and loss of mitochondrial potential, which may promote the association of parkin with mitochondria (311).”
From Redox regulation of mitochondrial function (2012) · cites this paper as [107]
Parkin and Pink1 also seem to be involved in mitochondrial quality control by promoting the removal of damaged mitochondria by autophagy in human cells.
“Adding to the complexity of the role of Parkin and Pink1 in PD pathogenesis, these proteins also seem to be involved in mitochondrial quality control by promoting the removal of damaged mitochondria by autophagy in human cells (Dagda et al., 2009; Narendra et al., 2008).”
From New insights into the role of mitochondria in aging: mitochondrial dynamics and more (2010) · cites this paper as Dagda et al., 2009
PINK1 deficit leads to swelling, shortening, and fragmentation of mitochondria as a result of inhibited Complex I enzyme activity.
“Experimental studies employing cell lines revealed that PINK1 deficit leads to swelling, shortening (Dagda et al. 2009), and fragmentation of mitochondria as a result of inhibited Complex I enzyme activity (Gegg et al. 2009).”
From Reactive Oxygen Species, Toxicity, Oxidative Stress, and Antioxidants: Chronic Diseases and Aging (2023) · cites this paper as Dagda et al. 2009
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- Authors
- Dagda, R. K., Cherra, S. J., Kulich, S. M., Tandon, A., Park, D., & Chu, C. T.
- Affiliations
- University of Pittsburgh (US)
- University of Toronto (CA)
- University of Ottawa (CA)
- Corresponding author
- Chu, Charleen T.
- Venue
- Journal of Biological Chemistry
- Publisher
- Elsevier BV
- Published
- 2009-05
- Volume
- 284
- Issue
- 20
- Pages
- 13843-13855
- ISSN
- 0021-9258 (ISSN-L)
- PMC
- PMC2679485
- OpenAlex
- W2154887758
- Cited by
- 954
- References
- 61
- Citations by year
- 2026: 17 · 2025: 36 · 2024: 30 · 2023: 48 · 2022: 59 · 2021: 61 · 2020: 59 · 2019: 53 · 2018: 64 · 2017: 68 · 2016: 47 · 2015: 47 · 2014: 58 · 2013: 62 · 2012: 68
- FWCI
- 52.06
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- Locations
- Journal of Biological Chemistry (publishedVersion, cc-by)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Funders
- Pittsburgh Foundation
- American Parkinson Disease Association
- University of Pittsburgh
- National Institutes of Health
- National Institute on Aging (AG026389, F32AG030821, R01AG026389)
- National Institute on Deafness and Other Communication Disorders (DC009120, K18DC009120)
- National Institute of Neurological Disorders and Stroke (NS05377, R21NS053777)
- Topics
- Health Sciences › Medicine › Neurology › Parkinson's Disease Mechanisms and Treatments
- Health Sciences › Medicine › Epidemiology › Autophagy in Disease and Therapy
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Mitochondrial Function and Pathology
- Keywords
- PINK1, mitophagy, mitochondrial fission, oxidative stress, mitochondrial fragmentation, autophagy, Parkin, Drp1, ATG7, LC3, mitochondrial homeostasis, Parkinson's disease, neuronal cell death, SH-SY5Y cells
- MeSH terms
- Autophagy-Related Protein 7, PTEN-Induced Putative Kinase, Autophagy, Homeostasis, Humans, Microtubule-Associated Proteins, Mitochondria, Parkinson Disease, Protein Kinases, Oxidative Stress, Ubiquitin-Activating Enzymes, Ubiquitin-Protein Ligases, Gene Knockdown Techniques
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