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Proteasome and p97 mediate mitophagy and degradation of mitofusins induced by Parkin

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 depolarizatio...

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Autores principales: Tanaka, Atsushi, Cleland, Megan M., Xu, Shan, Narendra, Derek P., Suen, Der-Fen, Karbowski, Mariusz, Youle, Richard J.
Formato: Texto
Lenguaje:English
Publicado: The Rockefeller University Press 2010
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3010068/
https://www.ncbi.nlm.nih.gov/pubmed/21173115
http://dx.doi.org/10.1083/jcb.201007013
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author Tanaka, Atsushi
Cleland, Megan M.
Xu, Shan
Narendra, Derek P.
Suen, Der-Fen
Karbowski, Mariusz
Youle, Richard J.
author_facet Tanaka, Atsushi
Cleland, Megan M.
Xu, Shan
Narendra, Derek P.
Suen, Der-Fen
Karbowski, Mariusz
Youle, Richard J.
author_sort Tanaka, Atsushi
collection PubMed
description 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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spelling pubmed-30100682011-06-27 Proteasome and p97 mediate mitophagy and degradation of mitofusins induced by Parkin Tanaka, Atsushi Cleland, Megan M. Xu, Shan Narendra, Derek P. Suen, Der-Fen Karbowski, Mariusz Youle, Richard J. J Cell Biol Research Articles 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. The Rockefeller University Press 2010-12-27 /pmc/articles/PMC3010068/ /pubmed/21173115 http://dx.doi.org/10.1083/jcb.201007013 Text en This article is distributed under the terms of an Attribution–Noncommercial–Share Alike–No Mirror Sites license for the first six months after the publication date (see http://www.rupress.org/terms). After six months it is available under a Creative Commons License (Attribution–Noncommercial–Share Alike 3.0 Unported license, as described at http://creativecommons.org/licenses/by-nc-sa/3.0/).
spellingShingle Research Articles
Tanaka, Atsushi
Cleland, Megan M.
Xu, Shan
Narendra, Derek P.
Suen, Der-Fen
Karbowski, Mariusz
Youle, Richard J.
Proteasome and p97 mediate mitophagy and degradation of mitofusins induced by Parkin
title Proteasome and p97 mediate mitophagy and degradation of mitofusins induced by Parkin
title_full Proteasome and p97 mediate mitophagy and degradation of mitofusins induced by Parkin
title_fullStr Proteasome and p97 mediate mitophagy and degradation of mitofusins induced by Parkin
title_full_unstemmed Proteasome and p97 mediate mitophagy and degradation of mitofusins induced by Parkin
title_short Proteasome and p97 mediate mitophagy and degradation of mitofusins induced by Parkin
title_sort proteasome and p97 mediate mitophagy and degradation of mitofusins induced by parkin
topic Research Articles
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3010068/
https://www.ncbi.nlm.nih.gov/pubmed/21173115
http://dx.doi.org/10.1083/jcb.201007013
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