AMBRA1 is able to induce mitophagy via LC3 binding, regardless of PARKIN and p62/SQSTM1

Cell Death Differ. 2015 Mar;22(3):419-32. doi: 10.1038/cdd.2014.139. Epub 2014 Sep 12.

Abstract

Damaged mitochondria are eliminated by mitophagy, a selective form of autophagy whose dysfunction associates with neurodegenerative diseases. PINK1, PARKIN and p62/SQTMS1 have been shown to regulate mitophagy, leaving hitherto ill-defined the contribution by key players in 'general' autophagy. In basal conditions, a pool of AMBRA1 - an upstream autophagy regulator and a PARKIN interactor - is present at the mitochondria, where its pro-autophagic activity is inhibited by Bcl-2. Here we show that, upon mitophagy induction, AMBRA1 binds the autophagosome adapter LC3 through a LIR (LC3 interacting region) motif, this interaction being crucial for regulating both canonical PARKIN-dependent and -independent mitochondrial clearance. Moreover, forcing AMBRA1 localization to the outer mitochondrial membrane unleashes a massive PARKIN- and p62-independent but LC3-dependent mitophagy. These results highlight a novel role for AMBRA1 as a powerful mitophagy regulator, through both canonical or noncanonical pathways.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adaptor Proteins, Signal Transducing / metabolism*
  • Animals
  • Autophagy / physiology*
  • HEK293 Cells
  • HeLa Cells
  • Heat-Shock Proteins / metabolism
  • Humans
  • Mice
  • Mice, Transgenic
  • Microtubule-Associated Proteins / metabolism*
  • Mitochondria / metabolism*
  • Neurodegenerative Diseases / metabolism*
  • Sequestosome-1 Protein
  • Transfection
  • Ubiquitin-Protein Ligases / metabolism*

Substances

  • AMBRA1 protein, human
  • Adaptor Proteins, Signal Transducing
  • Ambra1 protein, mouse
  • Heat-Shock Proteins
  • MAP1LC3A protein, human
  • Map1lc3b protein, mouse
  • Microtubule-Associated Proteins
  • SQSTM1 protein, human
  • Sequestosome-1 Protein
  • Sqstm1 protein, mouse
  • Ubiquitin-Protein Ligases
  • parkin protein