USP8 regulates mitophagy by removing K6‐linked ubiquitin conjugates from parkin
Open accessAbstract
Mutations in the Park2 gene, encoding the E3 ubiquitin-ligase parkin, are responsible for a familial form of Parkinson's disease (PD). Parkin-mediated ubiquitination is critical for the efficient elimination of depolarized dysfunctional mitochondria by autophagy (mitophagy). As damaged mitochondria are a major source of toxic reactive oxygen species within the cell, this pathway is believed to be highly relevant to the pathogenesis of PD. Little is known about how parkin-mediated ubiquitination is regulated during mitophagy or about the nature of the ubiquitin conjugates involved. We report here that USP8/UBPY, a deubiquitinating enzyme not previously implicated in mitochondrial quality control, is critical for parkin-mediated mitophagy. USP8 preferentially removes non-canonical K6-linked ubiquitin chains from parkin, a process required for the efficient recruitment of parkin to depolarized mitochondria and for their subsequent elimination by mitophagy. This work uncovers a novel role for USP8-mediated deubiquitination of K6-linked ubiquitin conjugates from parkin in mitochondrial quality control.
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Abnormal parkin ubiquitination prevents its proteasomal degradation and impedes parkin-mediated mitophagy.
“abnormal parkin ubiquitination was shown to prevent its proteasomal degradation and impede parkin-mediated mitophagy44.”
From Altered mitochondrial dynamics and function in APOE4-expressing astrocytes (2020) · cites this paper as [44]
The paper reports that increased K6-linked ubiquitin conjugates on parkin delay parkin-mediated mitophagy (figure legend, “Viral-mediated infection and lysis of cortical neurons”; page unavailable). It also reports that reduced USP8 activity appears to protect parkin from degradation, but says K6-linked ubiquitination is *likely* to protect it from degradation in the proteasome **or lysosome** (“USP8 selectively removes K6-linked ubiquitin conjugates from parkin” and discussion; pages unavailable). The claim overstates this as demonstrated prevention of proteasomal degradation specifically. (LLM, conf=0.88)
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- Authors
- Durcan, T. M., Tang, M. Y., Pérusse, J. R., Dashti, E. A., Aguileta, M. A., McLelland, G., Gros, P., Shaler, T. A., Faubert, D., Coulombe, B., & Fon, E. A.
- Affiliations
- Montreal Neurological Institute and Hospital (CA)
- Montreal Clinical Research Institute (CA)
- SRI International (US)
- Corresponding author
- Fon, Edward A
- ORCID
- Venue
- The EMBO Journal
- Published
- 2014-09-12
- Volume
- 33
- Issue
- 21
- Pages
- 2473-2491
- ISSN
- 0261-4189 (ISSN-L)
- 1460-2075
- PMC
- PMC4283406
- OpenAlex
- W2113190139
- Cited by
- 375
- References
- 10
- Citations by year
- 2026: 25 · 2025: 22 · 2024: 35 · 2023: 36 · 2022: 33 · 2021: 37 · 2020: 42 · 2019: 31 · 2018: 24 · 2017: 33 · 2016: 26 · 2015: 27 · 2014: 3
- FWCI
- 11.20
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- The EMBO Journal (publishedVersion)
- Europe PMC (PubMed Central) (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Funders
- Parkinson's Society of Canada
- CIHR Operating grant (MOP‐62714)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Ubiquitin and proteasome pathways
- Health Sciences › Medicine › Epidemiology › Autophagy in Disease and Therapy
- Health Sciences › Medicine › Neurology › Parkinson's Disease Mechanisms and Treatments
- Keywords
- USP8, Parkin, mitophagy, deubiquitination, mitochondrial quality control, Parkinson's disease, E3 ubiquitin ligase, mitochondrial depolarization, autophagy
- MeSH terms
- HeLa Cells, Humans, Mitochondria, Endopeptidases, Ubiquitin Thiolesterase, Ubiquitin-Protein Ligases, Ubiquitination, Endosomal Sorting Complexes Required for Transport, HEK293 Cells, Mitophagy
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