Cited by 1,969Parkinson's Disease Mechanisms and TreatmentsAutophagy in Disease and TherapyNuclear Receptors and Signaling

PINK1 stabilized by mitochondrial depolarization recruits Parkin to damaged mitochondria and activates latent Parkin for mitophagy

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Matsuda, Noriyuki, Sato, Shigeto, Shiba, Kahori, Okatsu, Kei, Saisho, Keiko, Gautier, Clement A., Sou, Yu-shin, Saiki, Shinji +6 more·2010·Journal of Cell Biology

Abstract

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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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
Venue
Journal of Cell Biology
Published
2010-04-19
Volume
189
Issue
2
Pages
211-221
ISSN
  • 0021-9525 (ISSN-L)
  • 1540-8140
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
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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