title: AMBRA1 is able to induce mitophagy via LC3 binding, regardless of PARKIN and p62/SQSTM1.
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.
authors.affiliation: 1] IRCCS Fondazione Santa Lucia, Rome, Italy [2] Department of Biology, University of Rome Tor Vergata, Rome, Italy.
authors.forename: F
authors.initials: F
authors.lastname: Strappazzon
authors.affiliation: IRCCS Fondazione Santa Lucia, Rome, Italy.
authors.forename: F
authors.initials: F
authors.lastname: Nazio
authors.affiliation: 1] IRCCS Fondazione Santa Lucia, Rome, Italy [2] Dulbecco-Telethon Institute, Venetian Institute of Molecular Medicine, Padova, Italy.
authors.forename: M
authors.initials: M
authors.lastname: Corrado
authors.affiliation: 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.
authors.forename: V
authors.initials: V
authors.lastname: Cianfanelli
authors.affiliation: IRCCS Istituto Nazionale Malattie Infettive Lazzaro Spallanzani, Rome, Italy.
authors.forename: A
authors.initials: A
authors.lastname: Romagnoli
authors.affiliation: 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.
authors.forename: G M
authors.initials: GM
authors.lastname: Fimia
authors.affiliation: IRCCS Fondazione Santa Lucia, Rome, Italy.
authors.forename: S
authors.initials: S
authors.lastname: Campello
authors.affiliation: IRCCS Istituto Nazionale Malattie Infettive Lazzaro Spallanzani, Rome, Italy.
authors.forename: R
authors.initials: R
authors.lastname: Nardacci
authors.affiliation: 1] Department of Biology, University of Rome Tor Vergata, Rome, Italy [2] IRCCS Istituto Nazionale Malattie Infettive Lazzaro Spallanzani, Rome, Italy.
authors.forename: M
authors.initials: M
authors.lastname: Piacentini
authors.affiliation: 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.
authors.forename: M
authors.initials: M
authors.lastname: Campanella
authors.affiliation: 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.
authors.forename: F
authors.initials: F
authors.lastname: Cecconi
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000378:metabolism*; D000818:Animals; D001343:Autophagy / Q000502:physiology*; D057809:HEK293 Cells; D006367:HeLa Cells; D006360:Heat-Shock Proteins / Q000378:metabolism; D006801:Humans; D051379:Mice; D008822:Mice, Transgenic; D008869:Microtubule-Associated Proteins / Q000378:metabolism*; D008928:Mitochondria / Q000378:metabolism*; D019636:Neurodegenerative Diseases / Q000378:metabolism*; D000071456:Sequestosome-1 Protein; D014162:Transfection; D044767:Ubiquitin-Protein Ligases / Q000378:metabolism*
chemical_list: C553334:AMBRA1 protein, human; D048868:Adaptor Proteins, Signal Transducing; C521754:Ambra1 protein, mouse; D006360:Heat-Shock Proteins; C477012:MAP1LC3A protein, human; C480860:Map1lc3b protein, mouse; D008869:Microtubule-Associated Proteins; C099718:SQSTM1 protein, human; D000071456:Sequestosome-1 Protein; C101343:Sqstm1 protein, mouse; D044767:Ubiquitin-Protein Ligases; C111567:parkin protein