Burman, JL;
Pickles, S;
Wang, C;
Sekine, S;
Vargas, JNS;
Zhang, Z;
Youle, AM;
... Youle, RJ; + view all
(2017)
Mitochondrial fission facilitates the selective mitophagy of protein aggregates.
Journal of Cell Biology
, 216
(10)
pp. 3231-3247.
10.1083/jcb.201612106.
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Abstract
Within the mitochondrial matrix, protein aggregation activates the mitochondrial unfolded protein response and PINK1–Parkin-mediated mitophagy to mitigate proteotoxicity. We explore how autophagy eliminates protein aggregates from within mitochondria and the role of mitochondrial fission in mitophagy. We show that PINK1 recruits Parkin onto mitochondrial subdomains after actinonin-induced mitochondrial proteotoxicity and that PINK1 recruits Parkin proximal to focal misfolded aggregates of the mitochondrial-localized mutant ornithine transcarbamylase (ΔOTC). Parkin colocalizes on polarized mitochondria harboring misfolded proteins in foci with ubiquitin, optineurin, and LC3. Although inhibiting Drp1-mediated mitochondrial fission suppresses the segregation of mitochondrial subdomains containing ΔOTC, it does not decrease the rate of ΔOTC clearance. Instead, loss of Drp1 enhances the recruitment of Parkin to fused mitochondrial networks and the rate of mitophagy as well as decreases the selectivity for ΔOTC during mitophagy. These results are consistent with a new model that, instead of promoting mitophagy, fission protects healthy mitochondrial domains from elimination by unchecked PINK1–Parkin activity.
| Type: | Article |
|---|---|
| Title: | Mitochondrial fission facilitates the selective mitophagy of protein aggregates |
| Open access status: | An open access version is available from UCL Discovery |
| DOI: | 10.1083/jcb.201612106 |
| Publisher version: | https://doi.org/10.1083/jcb.201612106 |
| Language: | English |
| Additional information: | © 2021 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 4.0 International license, as described at https://creativecommons.org/licenses/by-nc-sa/4.0/). |
| Keywords: | Cell death and autophagy, Cell metabolism, Disease |
| UCL classification: | UCL UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Brain Sciences UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Brain Sciences > UCL Queen Square Institute of Neurology UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Brain Sciences > UCL Queen Square Institute of Neurology > Department of Neuromuscular Diseases |
| URI: | https://discovery.ucl.ac.uk/id/eprint/10125667 |
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