Parkin Mediates Proteasome-dependent Protein Degradation and Rupture of the Outer Mitochondrial Membrane
Open accessAbstract
Upon mitochondrial depolarization, Parkin, a Parkinson disease-related E3 ubiquitin ligase, translocates from the cytosol to mitochondria and promotes their degradation by mitophagy, a selective type of autophagy. Here, we report that in addition to mitophagy, Parkin mediates proteasome-dependent degradation of outer membrane proteins such as Tom20, Tom40, Tom70, and Omp25 of depolarized mitochondria. By contrast, degradation of the inner membrane and matrix proteins largely depends on mitophagy. Furthermore, Parkin induces rupture of the outer membrane of depolarized mitochondria, which also depends on proteasomal activity. Upon induction of mitochondrial depolarization, proteasomes are recruited to mitochondria in the perinuclear region. Neither proteasome-dependent degradation of outer membrane proteins nor outer membrane rupture is required for mitophagy. These results suggest that Parkin regulates degradation of outer and inner mitochondrial membrane proteins differently through proteasome- and mitophagy-dependent pathways.
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Ubiquitination/proteasomal degradation of Mfn1 and Tom40, as well as of total mitochondrial ubiquitin, are reduced in APOE4 astrocytes.
“the ubiquitination/proteasomal degradation of Mfn1 and Tom408,35, as well as of total mitochondrial ubiquitin, are reduced in the APOE4 astrocytes”
From Altered mitochondrial dynamics and function in APOE4-expressing astrocytes (2020) · cites this paper as [35]
The OMM Protein Degradation Is Inhibited by Proteasome Inhibitors section reports proteasome-dependent Tom40 degradation, and the Discussion reports proteasome-dependent mitofusin 1 degradation. But the Discussion says it is unknown whether these proteins are directly ubiquitinated by Parkin. The APOE4-astrocyte reduction is the citing authors’ own finding, not a result attributed to this source by the citation placement. (LLM, conf=0.85)
Experimental — accuracy not yet measuredTom20 and Tom70 have been associated with Parkinson's disease-linked parkin and ALS-linked SOD1.
“Additionally, Tom20 and Tom70 have been associated to Parkinson's disease-linked parkin and ALS-linked SOD1 (64,65).”
From Functional genomic screen and network analysis reveal novel modifiers of tauopathy dissociated from tau phosphorylation (2011) · cites this paper as [64]
Levels of Tom40 and Tom20 are higher in APOE4 astrocytes.
“the levels of two other mitochondrial parkin substrates, namely Tom40 and Tom2035, exhibited higher levels in APOE4 astrocytes (Fig. S2d).”
From Altered mitochondrial dynamics and function in APOE4-expressing astrocytes (2020) · cites this paper as [35]
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- Authors
- Yoshii, S. R., Kishi, C., Ishihara, N., & Mizushima, N.
- Affiliations
- Tokyo Medical and Dental University (JP)
- Kurume University (JP)
- Corresponding author
- Mizushima, Noboru
- Venue
- Journal of Biological Chemistry
- Publisher
- Elsevier BV
- Published
- 2011-06
- Volume
- 286
- Issue
- 22
- Pages
- 19630-19640
- ISSN
- 0021-9258 (ISSN-L)
- PMC
- PMC3103342
- OpenAlex
- W2014459126
- Cited by
- 612
- References
- 9
- Citations by year
- 2026: 17 · 2025: 16 · 2024: 35 · 2023: 31 · 2022: 37 · 2021: 39 · 2020: 58 · 2019: 43 · 2018: 53 · 2017: 41 · 2016: 42 · 2015: 42 · 2014: 46 · 2013: 46 · 2012: 51
- FWCI
- 37.68
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- Locations
- Journal of Biological Chemistry (publishedVersion, cc-by)
- Europe PMC (PubMed Central) (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Funders
- Takeda Science Foundation
- Ministry of Education, Culture, Sports, Science and Technology
- University of Tokyo
- Japan Society for the Promotion of Science
- Topics
- Health Sciences › Medicine › Epidemiology › Autophagy in Disease and Therapy
- Health Sciences › Medicine › Neurology › Parkinson's Disease Mechanisms and Treatments
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Ubiquitin and proteasome pathways
- Keywords
- Parkin, proteasomal degradation, mitophagy, mitochondrial depolarization, E3 ubiquitin ligase, Tom20, Tom40, Tom70, Omp25, mitochondrial membrane proteins, Parkinson's disease, selective autophagy
- MeSH terms
- Animals, Cells, Cultured, Membrane Proteins, Mice, Knockout, Mitochondrial Proteins, Ubiquitin-Protein Ligases, Proteasome Endopeptidase Complex, Mitochondrial Membranes, Mice
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