A Rab5 endosomal pathway mediates Parkin-dependent mitochondrial clearance

Babette C. Hammerling, Rita H. Najor, Melissa Q. Cortez, Sarah E. Shires, Leonardo J. Leon, Eileen R. Gonzalez, Daniela Boassa, Sébastien Phan, Andrea Thor, Rebecca E. Jimenez, Hong Li, Richard N. Kitsis, Gerald W. Dorn, Junichi Sadoshima, Mark H. Ellisman and Åsa B. Gustafsson ()
Additional contact information
Babette C. Hammerling: Skaggs School of Pharmacy and Pharmaceutical Sciences, University of California San Diego
Rita H. Najor: Skaggs School of Pharmacy and Pharmaceutical Sciences, University of California San Diego
Melissa Q. Cortez: Skaggs School of Pharmacy and Pharmaceutical Sciences, University of California San Diego
Sarah E. Shires: Skaggs School of Pharmacy and Pharmaceutical Sciences, University of California San Diego
Leonardo J. Leon: Skaggs School of Pharmacy and Pharmaceutical Sciences, University of California San Diego
Eileen R. Gonzalez: Skaggs School of Pharmacy and Pharmaceutical Sciences, University of California San Diego
Daniela Boassa: Center for Research in Biological Systems, National Center for Microscopy and Imaging Research, University of California San Diego
Sébastien Phan: Center for Research in Biological Systems, National Center for Microscopy and Imaging Research, University of California San Diego
Andrea Thor: Center for Research in Biological Systems, National Center for Microscopy and Imaging Research, University of California San Diego
Rebecca E. Jimenez: Skaggs School of Pharmacy and Pharmaceutical Sciences, University of California San Diego
Hong Li: Rutgers New Jersey Medical School
Richard N. Kitsis: Albert Einstein College of Medicine
Gerald W. Dorn: Washington University School of Medicine
Junichi Sadoshima: Rutgers New Jersey Medical School
Mark H. Ellisman: Center for Research in Biological Systems, National Center for Microscopy and Imaging Research, University of California San Diego
Åsa B. Gustafsson: Skaggs School of Pharmacy and Pharmaceutical Sciences, University of California San Diego

Nature Communications, 2017, vol. 8, issue 1, 1-16

Abstract: 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.

Date: 2017
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DOI: 10.1038/ncomms14050

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