Broad activation of the ubiquitin–proteasome system by Parkin is critical for mitophagy
Open accessAbstract
Parkin, an E3 ubiquitin ligase implicated in Parkinson's disease, promotes degradation of dysfunctional mitochondria by autophagy. Using proteomic and cellular approaches, we show that upon translocation to mitochondria, Parkin activates the ubiquitin-proteasome system (UPS) for widespread degradation of outer membrane proteins. This is evidenced by an increase in K48-linked polyubiquitin on mitochondria, recruitment of the 26S proteasome and rapid degradation of multiple outer membrane proteins. The degradation of proteins by the UPS occurs independently of the autophagy pathway, and inhibition of the 26S proteasome completely abrogates Parkin-mediated mitophagy in HeLa, SH-SY5Y and mouse cells. Although the mitofusins Mfn1 and Mfn2 are rapid degradation targets of Parkin, we find that degradation of additional targets is essential for mitophagy. These results indicate that remodeling of the mitochondrial outer membrane proteome is important for mitophagy, and reveal a causal link between the UPS and autophagy, the major pathways for degradation of intracellular substrates.
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The positive effect of mitochondrial uncoupling on autophagy has been established in many cellular and animal models, including adipocytes, MEFs, HeLa cells, HepG2 cells, SH-SY5Y neuroblastoma cells, and C57BL6 mice.
“The positive effect of mitochondrial uncoupling on autophagy has been established in many cellular and animal models, including adipocytes [91], MEFs [92], HeLa cells [93], HepG2 cells [90], SH-SY5Y neuroblastoma cells [93], or C57BL6 mice [94].”
From Mitochondrial Uncoupling: A Key Controller of Biological Processes in Physiology and Diseases (2019) · cites this paper as [93]
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- Authors
- Chan, N. C., Salazar, A. M., Pham, A. H., Sweredoski, M. J., Kolawa, N. J., Graham, R. L. J., Hess, S., & Chan, D. C.
- Affiliations
- California Institute of Technology (US)
- Howard Hughes Medical Institute (US)
- Corresponding author
- Chan, David C.
- Venue
- Human Molecular Genetics
- Publisher
- Oxford University Press (OUP)
- Published
- 2011-02-04
- Volume
- 20
- Issue
- 9
- Pages
- 1726-1737
- ISSN
- 0964-6906 (ISSN-L)
- 1460-2083
- PMC
- PMC3071670
- OpenAlex
- W2130979925
- Cited by
- 993
- References
- 42
- Citations by year
- 2026: 28 · 2025: 36 · 2024: 56 · 2023: 43 · 2022: 53 · 2021: 80 · 2020: 79 · 2019: 62 · 2018: 67 · 2017: 51 · 2016: 75 · 2015: 72 · 2014: 97 · 2013: 81 · 2012: 75
- FWCI
- 68.89
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- cc-by-nc
- Locations
- Human Molecular Genetics (publishedVersion, cc-by-nc)
- Europe PMC (PubMed Central) (publishedVersion, cc-by-nc)
- PubMed Central (publishedVersion, cc-by-nc)
- PubMed (publishedVersion)
- Research Explorer (The University of Manchester) (publishedVersion)
- CaltechAUTHORS (California Institute of Technology) (submittedVersion, cc-by-nc)
- Research Portal (Queen's University Belfast) (submittedVersion)
- Funders
- Howard Hughes Medical Institute
- National Institute of General Medical Sciences (R01GM062967, GM062967)
- Topics
- Health Sciences › Medicine › Epidemiology › Autophagy in Disease and Therapy
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Ubiquitin and proteasome pathways
- Health Sciences › Medicine › Neurology › Parkinson's Disease Mechanisms and Treatments
- Keywords
- Parkin, ubiquitin-proteasome system, mitophagy, Parkinson's disease, mitochondrial outer membrane proteins, 26S proteasome, K48-linked polyubiquitin, mitofusins, Mfn1, mitofusin 2, mitochondrial protein degradation, autophagy
- MeSH terms
- Animals, Autophagy, Cell Line, Humans, Mitochondria, Parkinson Disease, Mitochondrial Proteins, Ubiquitin, Ubiquitin-Protein Ligases, Proteasome Endopeptidase Complex, Mice
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