The DOI matches its Crossref record; 57 of the 57 references it cites were found in a registry or an index.
Proteasome and p97 mediate mitophagy and degradation of mitofusins induced by Parkin
Open accessAbstract
Damage to mitochondria can lead to the depolarization of the inner mitochondrial membrane, thereby sensitizing impaired mitochondria for selective elimination by autophagy. However, fusion of uncoupled mitochondria with polarized mitochondria can compensate for damage, reverse membrane depolarization, and obviate mitophagy. Parkin, an E3 ubiquitin ligase that is mutated in monogenic forms of Parkinson’s disease, was recently found to induce selective autophagy of damaged mitochondria. Here we show that ubiquitination of mitofusins Mfn1 and Mfn2, large GTPases that mediate mitochondrial fusion, is induced by Parkin upon membrane depolarization and leads to their degradation in a proteasome- and p97-dependent manner. p97, a AAA+ ATPase, accumulates on mitochondria upon uncoupling of Parkin-expressing cells, and both p97 and proteasome activity are required for Parkin-mediated mitophagy. After mitochondrial fission upon depolarization, Parkin prevents or delays refusion of mitochondria, likely by the elimination of mitofusins. Inhibition of Drp1-mediated mitochondrial fission, the proteasome, or p97 prevents Parkin-induced mitophagy.
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“p97 provides the driving force to extract Mfn1, Mfn2, and the anti-apoptotic protein MCL1 from the OMM and chaperone them to the proteasome [49, 50].”
From The connection between the dynamic remodeling of the mitochondrial network and the regulation of muscle mass (2021) · cites this paper as [49]
In the citing paper
“p97/VCP is critical in the retrotranslocation and degradation of endoplasmic reticulum-associated proteins (ERAD) [47] and mitochondrial proteins ( MAD) [49, 50].”
From The connection between the dynamic remodeling of the mitochondrial network and the regulation of muscle mass (2021) · cites this paper as [49]
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“Parkin inhibits refusion after mitochondrial fission upon depolarization by inducing the proteasomal degradation of mitofusins (97).”
From From mitochondria to sarcopenia: role of 17β-estradiol and testosterone (2023) · cites this paper as [97]
In the citing paper
“Latent Parkin, in the cytosol, is activated and relocalized to the outer mitochondrial membrane, ubiquitinating mitochondrial proteins such as Mitofusin and Miro (Liu et al., 2012, Tanaka et al., 2010, Wang et al., 2011).”
From A Cell-Based High-Throughput Screening Identified Two Compounds that Enhance PINK1-Parkin Signaling (2020) · cites this paper as Tanaka et al., 2010
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Metadata
- Authors
- Tanaka, A., Cleland, M. M., Xu, S., Narendra, D. P., Suen, D.-F., Karbowski, M., & Youle, R. J.
- Affiliations
- National Institutes of Health (US)
- Biochemistry Section, Surgical Neurology Branch, National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, MD 20892 1
- University of Maryland, Baltimore (US)
- Corresponding author
- Karbowski, Mariusz
- Venue
- Journal of Cell Biology
- Publisher
- Rockefeller University Press
- Published
- 2010-12-20
- Volume
- 191
- Issue
- 7
- Pages
- 1367-1380
- ISSN
- 0021-9525 (ISSN-L)
- 1540-8140
- PMC
- PMC3010068
- OpenAlex
- W2104412320
- Cited by
- 1,369
- References
- 57
- Citations by year
- 2026: 48 · 2025: 58 · 2024: 68 · 2023: 68 · 2022: 84 · 2021: 108 · 2020: 111 · 2019: 101 · 2018: 78 · 2017: 85 · 2016: 99 · 2015: 85 · 2014: 111 · 2013: 110 · 2012: 97
- FWCI
- 60.98
- 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)
- Funders
- National Institutes of Health
- Japan Society for the Promotion of Science
- National Institute of General Medical Sciences (R01GM083131)
- National Institute of Neurological Disorders and Stroke
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cell Biology › Autophagy in Disease and Therapy
- Health Sciences › Medicine › Clinical Neurology › Parkinson's Disease Mechanisms and Treatments
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Ubiquitin and proteasome pathways
- Keywords
- mitophagy, Parkin, mitofusins, Mfn1, mitofusin 2, proteasome, VCP, AAA+ ATPase, mitochondrial fusion, mitochondrial fission, Drp1, mitochondrial depolarization, ubiquitination, selective autophagy, Parkinson's disease, ubiquitin-proteasome system
- MeSH terms
- PTEN-Induced Putative Kinase, Adenosine Triphosphatases, Animals, Autophagy, Carbonyl Cyanide m-Chlorophenyl Hydrazone, Fibroblasts, HeLa Cells, Humans, Leupeptins, Membrane Fusion, Membrane Proteins, Microtubule-Associated Proteins, Mitochondria, Models, Biological, Nuclear Proteins, Protein Binding, Protein Kinases, Mice, Knockout, GTP Phosphohydrolases, Mitochondrial Proteins, Membrane Transport Proteins, Mitochondrial Membrane Transport Proteins, Dynamins, RNA, Small Interfering, Ubiquitin-Conjugating Enzymes, Ubiquitin-Protein Ligases, HCT116 Cells, Cell Line, Tumor, Proteasome Endopeptidase Complex, Mice, Membrane Potential, Mitochondrial, Ubiquitination, Proteasome Inhibitors
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