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Broad activation of the ubiquitin-proteasome system by Parkin is critical for mitophagy

Chan, Nickie C. and Salazar, Anna M. and Pham, Anh H. and Sweredoski, Michael J. and Kolawa, Natalie J. and Graham, Robert L. J. and Hess, Sonja and Chan, David C. (2011) Broad activation of the ubiquitin-proteasome system by Parkin is critical for mitophagy. Human Molecular Genetics, 20 (9). pp. 1726-1737. ISSN 0964-6906. PMCID PMC3071670. https://resolver.caltech.edu/CaltechAUTHORS:20110504-073756492

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Abstract

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.


Item Type:Article
Related URLs:
URLURL TypeDescription
http://dx.doi.org/10.1093/hmg/ddr048DOIArticle
http://hmg.oxfordjournals.org/content/20/9/1726PublisherArticle
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3071670/PubMed CentralArticle
ORCID:
AuthorORCID
Sweredoski, Michael J.0000-0003-0878-3831
Hess, Sonja0000-0002-5904-9816
Additional Information:© 2011 The Author. Published by Oxford University Press. Received January 27, 2011; Revised and Accepted February 1, 2011. First published online: February 4, 2011. This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/ licenses/by-nc/2.5), which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited. We thank Ray Deshaies and the Chan lab for critical discussions and reading of the manuscript. We are grateful to Drs Yu-Shin Sou and Masaaki Komatsu for providing the Atg3-null MEFs, and to Willem den Besten and Ray Deshaies for providing ubiquitin plasmids. This work was supported by the National Institute of Health (GM062967) and the Thomas Hartman Foundation for Parkinson’s Research. Funding to pay the Open Access publication charges for this article was provided by the Howard Hughes Medical Institute.
Funders:
Funding AgencyGrant Number
NIHGM062967
Thomas Hartman Foundation for Parkinson's ResearchUNSPECIFIED
Howard Hughes Medical Institute (HHMI)UNSPECIFIED
Issue or Number:9
PubMed Central ID:PMC3071670
Record Number:CaltechAUTHORS:20110504-073756492
Persistent URL:https://resolver.caltech.edu/CaltechAUTHORS:20110504-073756492
Official Citation:Broad activation of the ubiquitin–proteasome system by Parkin is critical for mitophagy Hum. Mol. Genet. (2011) 20(9): 1726-1737 first published online February 4, 2011 doi:10.1093/hmg/ddr048
Usage Policy:This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/ licenses/by-nc/2.5), which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.
ID Code:23542
Collection:CaltechAUTHORS
Deposited By: Ruth Sustaita
Deposited On:05 May 2011 20:26
Last Modified:03 Oct 2019 02:47

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