A Rab5 endosomal pathway mediates Parkin-dependent mitochondrial clearance

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

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.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Animals
  • Apoptosis / physiology
  • Autophagy / physiology
  • Autophagy-Related Protein 5 / genetics
  • Autophagy-Related Protein 5 / metabolism
  • Beclin-1 / metabolism
  • Cell Line
  • Endosomal Sorting Complexes Required for Transport / metabolism*
  • Endosomes / metabolism*
  • Endosomes / ultrastructure
  • Female
  • Fibroblasts
  • Gene Knockdown Techniques
  • Lysosomes / metabolism
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Microscopy, Electron
  • Mitochondria / metabolism*
  • Mitochondria / ultrastructure
  • Mitophagy / physiology*
  • Myocytes, Cardiac
  • Primary Cell Culture
  • RNA, Small Interfering / metabolism
  • Rats
  • Rats, Sprague-Dawley
  • Signal Transduction / physiology
  • Ubiquitin-Protein Ligases / genetics
  • Ubiquitin-Protein Ligases / metabolism*
  • Ubiquitination / physiology
  • rab5 GTP-Binding Proteins / metabolism*

Substances

  • Atg5 protein, mouse
  • Autophagy-Related Protein 5
  • Beclin-1
  • Becn1 protein, mouse
  • Becn1 protein, rat
  • Endosomal Sorting Complexes Required for Transport
  • RNA, Small Interfering
  • Ubiquitin-Protein Ligases
  • parkin protein
  • rab5 GTP-Binding Proteins