PINK1 stabilized by mitochondrial depolarization recruits Parkin to damaged mitochondria and activates latent Parkin for mitophagy
Open accessAbstract
Parkinson's disease (PD) is a prevalent neurodegenerative disorder. Recent identification of genes linked to familial forms of PD such as Parkin and PINK1 (PTEN-induced putative kinase 1) has revealed that ubiquitylation and mitochondrial integrity are key factors in disease pathogenesis. However, the exact mechanism underlying the functional interplay between Parkin-catalyzed ubiquitylation and PINK1-regulated mitochondrial quality control remains an enigma. In this study, we show that PINK1 is rapidly and constitutively degraded under steady-state conditions in a mitochondrial membrane potential-dependent manner and that a loss in mitochondrial membrane potential stabilizes PINK1 mitochondrial accumulation. Furthermore, PINK1 recruits Parkin from the cytoplasm to mitochondria with low membrane potential to initiate the autophagic degradation of damaged mitochondria. Interestingly, the ubiquitin ligase activity of Parkin is repressed in the cytoplasm under steady-state conditions; however, PINK1-dependent mitochondrial localization liberates the latent enzymatic activity of Parkin. Some pathogenic mutations of PINK1 and Parkin interfere with the aforementioned events, suggesting an etiological importance. These results provide crucial insight into the pathogenic mechanisms of PD.
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Upon mitochondrial damage, PINK1 is quickly stabilized on damaged mitochondria, leading to translocation of cytosolic Parkin to damaged mitochondria.
“Upon mitochondrial damage, PINK1 is quickly stabilized on damaged mitochondria, which leads to translocation of cytosolic Parkin to damaged mitochondria [11–13].”
From miR-27a and miR-27b regulate autophagic clearance of damaged mitochondria by targeting PTEN-induced putative kinase 1 (PINK1) (2016) · cites this paper as [13]
The most extensively studied mitophagy pathway involves the E3 ligase Parkin and PINK1.
“The most extensively studied mitophagy pathway involves the E3 ligase Parkin and PINK1 (Phosphatase and tensin homolog (PTEN)-induced kinase 1) [121,122,123,124,125].”
From Mitochondrial Dynamics and Mitophagy in Skeletal Muscle Health and Aging (2021) · cites this paper as [125]
PINK1-Parkin signaling maintains mitochondrial health.
“Early-onset Parkinson's disease-associated PINK1-Parkin signaling maintains mitochondrial health.”
From A Cell-Based High-Throughput Screening Identified Two Compounds that Enhance PINK1-Parkin Signaling (2020) · cites this paper as Matsuda et al., 2010
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- Authors
- Matsuda, N., Sato, S., Shiba, K., Okatsu, K., Saisho, K., Gautier, C. A., Sou, Y.-S., Saiki, S., Kawajiri, S., Sato, F., Kimura, M., Komatsu, M., Hattori, N., & Tanaka, K.
- Affiliations
- Tokyo Metropolitan Institute of Medical Science (JP)
- Juntendo University (JP)
- Center for Neurologic Diseases, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115 4
- Japan Science and Technology Agency (JP)
- Corresponding author
- Matsuda, Noriyuki
- Tanaka, Keiji
- ORCID
- Venue
- Journal of Cell Biology
- Publisher
- Rockefeller University Press
- Published
- 2010-04-19
- Volume
- 189
- Issue
- 2
- Pages
- 211-221
- ISSN
- 0021-9525 (ISSN-L)
- 1540-8140
- PMC
- PMC2856912
- OpenAlex
- W2138311396
- Cited by
- 1,969
- References
- 32
- Citations by year
- 2026: 98 · 2025: 115 · 2024: 118 · 2023: 121 · 2022: 144 · 2021: 152 · 2020: 175 · 2019: 131 · 2018: 123 · 2017: 100 · 2016: 110 · 2015: 118 · 2014: 119 · 2013: 116 · 2012: 101
- FWCI
- 65.66
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- cc-by-nc-sa
- Locations
- The Journal of Cell Biology (publishedVersion, cc-by-nc-sa)
- PubMed Central (publishedVersion, cc-by-nc-sa)
- PubMed (publishedVersion)
- Digital Access to Scholarship at Harvard (DASH) (Harvard University) (submittedVersion, cc-by)
- Funders
- Ministry of Education, Culture, Sports, Science and Technology
- National Institutes of Health
- Topics
- Health Sciences › Medicine › Neurology › Parkinson's Disease Mechanisms and Treatments
- Health Sciences › Medicine › Epidemiology › Autophagy in Disease and Therapy
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Nuclear Receptors and Signaling
- Keywords
- PINK1, Parkin, Parkinson's disease, mitophagy, mitochondrial membrane potential, mitochondrial depolarization, ubiquitination, ubiquitin ligase activity, mitochondrial quality control, PINK1 mutations, parkin mutations, protein stabilization
- MeSH terms
- PTEN-Induced Putative Kinase, Animals, Carbonyl Cyanide m-Chlorophenyl Hydrazone, Dimethyl Sulfoxide, Fibroblasts, Fluorescent Dyes, HeLa Cells, Humans, Mitochondria, Parkinson Disease, Protein Kinases, Recombinant Fusion Proteins, Solvents, Uncoupling Agents, Biomarkers, Receptors, Cytoplasmic and Nuclear, Mice, Knockout, Mitochondrial Proteins, Ubiquitin-Protein Ligases, Mice, Membrane Potential, Mitochondrial
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