Journal Article

A Rab5 endosomal pathway mediates Parkin-dependent mitochondrial clearance

Cortez, Melissa Q., Thor, Andrea, Sadoshima, Junichi, Dorn, Gerald W., Ellisman, Mark H., Leon, Leonardo J., Jimenez, Rebecca E., Li, Hong, Hammerling, Babette C., Phan, Sébastien, Shires, Sarah E., Boassa, Daniela, Gonzalez, Eileen R., Kitsis, Richard N., Gustafsson, Åsa B., Najor, Rita H.

2017

Overview

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. Damaged mitochondria are normally cleared through canonical and alternative autophagy pathways. Here, the authors report that mitochondria can be cleared through an autophagy-independent endosomal-lysosomal pathway that depends on Parkin-dependent sequestration of mitochondria in Rab5-positive early endosomes.

• Publisher: Nature Publishing Group UK,Nature Publishing Group,Nature Portfolio
• Subject: 13/1 / 13/106 / 13/109 / 13/51 / 13/89 / 14/19 / 14/28 / 38/77 / 42/44 / 631/80/313/1776 / 631/80/39/2348 / 631/80/642/333 / 82/80 / Animals / Apoptosis - physiology / Autophagy / Autophagy - physiology / Autophagy-Related Protein 5 - genetics / Autophagy-Related Protein 5 - metabolism / Beclin-1 - metabolism / Cardiomyocytes / Cell death / Cell Line / Clearances / Crosstalk / Degradation / Embryo fibroblasts / Endosomal Sorting Complexes Required for Transport - metabolism / Endosomes / Endosomes - metabolism / Endosomes - ultrastructure / Female / Fibroblasts / Gene Knockdown Techniques / Humanities and Social Sciences / Kinases / Lysosomes / Lysosomes - metabolism / Male / Mice / Mice, Inbred C57BL / Mice, Knockout / Microscopy, Electron / Mitochondria / Mitochondria - metabolism / Mitochondria - ultrastructure / Mitophagy - physiology / multidisciplinary / Myocytes / Myocytes, Cardiac / Organelles / Parkin protein / Parkinson's disease / Phagocytosis / Primary Cell Culture / Quality control / rab5 GTP-Binding Proteins - metabolism / Rats / Rats, Sprague-Dawley / RNA, Small Interfering - metabolism / Science / Signal Transduction - physiology / Ubiquitin / Ubiquitin-Protein Ligases - genetics / Ubiquitin-Protein Ligases - metabolism / Ubiquitination - physiology