Endosomal Rab cycles regulate Parkin-mediated mitophagy

Elife. 2018 Jan 23;7:e31326. doi: 10.7554/eLife.31326.

Abstract

Damaged mitochondria are selectively eliminated by mitophagy. Parkin and PINK1, gene products mutated in familial Parkinson's disease, play essential roles in mitophagy through ubiquitination of mitochondria. Cargo ubiquitination by E3 ubiquitin ligase Parkin is important to trigger selective autophagy. Although autophagy receptors recruit LC3-labeled autophagic membranes onto damaged mitochondria, how other essential autophagy units such as ATG9A-integrated vesicles are recruited remains unclear. Here, using mammalian cultured cells, we demonstrate that RABGEF1, the upstream factor of the endosomal Rab GTPase cascade, is recruited to damaged mitochondria via ubiquitin binding downstream of Parkin. RABGEF1 directs the downstream Rab proteins, RAB5 and RAB7A, to damaged mitochondria, whose associations are further regulated by mitochondrial Rab-GAPs. Furthermore, depletion of RAB7A inhibited ATG9A vesicle assembly and subsequent encapsulation of the mitochondria by autophagic membranes. These results strongly suggest that endosomal Rab cycles on damaged mitochondria are a crucial regulator of mitophagy through assembling ATG9A vesicles.

Keywords: Parkin; Rab7; autophagy; cell biology; human; mitochondria; ubiquitin.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Autophagy-Related Proteins / metabolism
  • Endosomes / enzymology*
  • Guanine Nucleotide Exchange Factors / metabolism*
  • HeLa Cells
  • Humans
  • Membrane Proteins / metabolism
  • Mitophagy*
  • Protein Interaction Maps
  • Ubiquitin-Protein Ligases / metabolism*
  • Vesicular Transport Proteins / metabolism
  • rab GTP-Binding Proteins / metabolism*
  • rab5 GTP-Binding Proteins / metabolism*

Substances

  • Atg9a protein, human
  • Autophagy-Related Proteins
  • Guanine Nucleotide Exchange Factors
  • Membrane Proteins
  • RABGEF1 protein, human
  • Vesicular Transport Proteins
  • rab7 protein
  • Ubiquitin-Protein Ligases
  • parkin protein
  • RAB5C protein, human
  • rab GTP-Binding Proteins
  • rab5 GTP-Binding Proteins