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 Ii, Junichi Sadoshima, Mark H. Ellisman, Åsa B. Gustafsson

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46 Scopus citations

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.

Original languageEnglish (US)
Article number14050
JournalNature Communications
Volume8
DOIs
StatePublished - Jan 30 2017

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ASJC Scopus subject areas

  • Chemistry(all)
  • Biochemistry, Genetics and Molecular Biology(all)
  • Physics and Astronomy(all)

Cite this

Hammerling, B. C., Najor, R. H., Cortez, M. Q., Shires, S. E., Leon, L. J., Gonzalez, E. R., Boassa, D., Phan, S., Thor, A., Jimenez, R. E., Li, H., Kitsis, R. N., Ii, G. W. D., Sadoshima, J., Ellisman, M. H., & Gustafsson, Å. B. (2017). A Rab5 endosomal pathway mediates Parkin-dependent mitochondrial clearance. Nature Communications, 8, [14050]. https://doi.org/10.1038/ncomms14050