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.
F Strappazzon  1 ,  F Nazio  2 ,  M Corrado  3 ,  V Cianfanelli  4 ,  A Romagnoli  5 ,  G M Fimia  6 ,  S Campello  2 ,  R Nardacci  5 ,  M Piacentini  7 ,  M Campanella  8 ,  F Cecconi  9
Affiliations
  • 1. 1] IRCCS Fondazione Santa Lucia, Rome, Italy [2] Department of Biology, University of Rome Tor Vergata, Rome, Italy.
  • 2. IRCCS Fondazione Santa Lucia, Rome, Italy.
  • 3. 1] IRCCS Fondazione Santa Lucia, Rome, Italy [2] Dulbecco-Telethon Institute, Venetian Institute of Molecular Medicine, Padova, Italy.
  • 4. 1] Department of Biology, University of Rome Tor Vergata, Rome, Italy [2] Unit of Cell Stress and Survival, Danish Cancer Society Research Center, Copenhagen, Denmark.
  • 5. IRCCS Istituto Nazionale Malattie Infettive Lazzaro Spallanzani, Rome, Italy.
  • 6. 1] IRCCS Istituto Nazionale Malattie Infettive Lazzaro Spallanzani, Rome, Italy [2] Department of Biological and Environmental Sciences and Technolgies (DiSTeBA), University of Salento, Lecce, Italy.
  • 7. 1] Department of Biology, University of Rome Tor Vergata, Rome, Italy [2] IRCCS Istituto Nazionale Malattie Infettive Lazzaro Spallanzani, Rome, Italy.
  • 8. 1] Department of Comparative Biomedical Sciences, The Royal Veterinary College, University of London and UCL Consortium for Mitochondrial Research (CfMR), London, UK [2] European Brain Research Institute (EBRI), Rita Levi-Montalcini Foundation, Rome, Italy.
  • 9. 1] IRCCS Fondazione Santa Lucia, Rome, Italy [2] Department of Biology, University of Rome Tor Vergata, Rome, Italy [3] Unit of Cell Stress and Survival, Danish Cancer Society Research Center, Copenhagen, Denmark.
PMID: 25215947 DOI: 10.1038/cdd.2014.139
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.