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Nat Commun. 2017 Jan 30;8:14050. doi: 10.1038/ncomms14050.

A Rab5 endosomal pathway mediates Parkin-dependent mitochondrial clearance.

Author information

1
Skaggs School of Pharmacy and Pharmaceutical Sciences, University of California San Diego, 9500 Gilman Drive 0758, La Jolla, California 92093, USA.
2
Center for Research in Biological Systems, National Center for Microscopy and Imaging Research, University of California San Diego, La Jolla, California 92093, USA.
3
Rutgers New Jersey Medical School, Newark, New Jersey 07103, USA.
4
Albert Einstein College of Medicine, Bronx, New York 10461, USA.
5
Washington University School of Medicine, St Louis, Missouri 63110, USA.

Abstract

Damaged mitochondria pose a lethal threat to cells that necessitates their prompt removal. The currently recognized mechanism for disposal of mitochondria is autophagy, where damaged organelles are marked for disposal via ubiquitylation by Parkin. Here we report a novel pathway for mitochondrial elimination, in which these organelles undergo Parkin-dependent sequestration into Rab5-positive early endosomes via the ESCRT machinery. Following maturation, these endosomes deliver mitochondria to lysosomes for degradation. Although this endosomal pathway is activated by stressors that also activate mitochondrial autophagy, endosomal-mediated mitochondrial clearance is initiated before autophagy. The autophagy protein Beclin1 regulates activation of Rab5 and endosomal-mediated degradation of mitochondria, suggesting cross-talk between these two pathways. Abrogation of Rab5 function and the endosomal pathway results in the accumulation of stressed mitochondria and increases susceptibility to cell death in embryonic fibroblasts and cardiac myocytes. These data reveal a new mechanism for mitochondrial quality control mediated by Rab5 and early endosomes.

PMID:
28134239
PMCID:
PMC5290275
DOI:
10.1038/ncomms14050
[Indexed for MEDLINE]
Free PMC Article

Conflict of interest statement

The authors declare no competing financial interests.

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