[en] PINK1 accumulation at the outer mitochondrial membrane (OMM) is a key event required to signal depolarized mitochondria to the autophagy machinery. How this early step is, in turn, modulated by autophagy proteins remains less characterized. Here, we show that, upon mitochondrial depolarization, the proautophagic protein AMBRA1 is recruited to the OMM and interacts with PINK1 and ATAD3A, a transmembrane protein that mediates mitochondrial import and degradation of PINK1. Downregulation of AMBRA1 expression results in reduced levels of PINK1 due to its enhanced degradation by the mitochondrial protease LONP1, which leads to a decrease in PINK1-mediated ubiquitin phosphorylation and mitochondrial PRKN/PARKIN recruitment. Notably, ATAD3A silencing rescues defective PINK1 accumulation in AMBRA1-deficient cells upon mitochondrial damage. Overall, our findings underline an upstream contribution of AMBRA1 in the control of PINK1-PRKN mitophagy by interacting with ATAD3A and promoting PINK1 stability. This novel regulatory element may account for changes of PINK1 levels in neuropathological conditions.Abbreviations: ACTB/β-actin: actin beta; AMBRA1: autophagy and beclin 1 regulator 1; ATAD3A: ATPase family AAA domain containing 3A; BCL2L1/BCL-xL: BCL2 like 1; CCCP: carbonyl cyanide m-chlorophenyl hydrazone; MAP1LC3/LC3: microtubule associated protein 1 light chain 3; OMA1: OMA1 zinc metallopeptidase; OMM: outer mitochondrial membrane; PARL: presenilin associated rhomboid like; PARP: poly(ADP-ribose) polymerase; PD: Parkinson disease; PINK1: PTEN induced kinase 1; PRKN/PARKIN: parkin RBR E3 ubiquitin protein ligase; SDHA: succinate dehydrogenase complex flavoprotein subunit A; TOMM70: translocase of outer mitochondrial membrane 70.
Disciplines :
Sciences de la santé humaine: Multidisciplinaire, généralités & autres
Auteur, co-auteur :
Di Rienzo, Martina; Institute for Infectious Diseases Irccs "L. Spallanzani", Rome, Italy > Department of Epidemiology, Preclinical Research and Advanced Diagnostics, National
Romagnoli, Alessandra; National Institute for Infectious Diseases Irccs "L. Spallanzani", Rome, Italy > Department of Epidemiology, Preclinical Research and Advanced Diagnostics
Ciccosanti, Fabiola; National Institute for Infectious Diseases Irccs "L. Spallanzani", Rome, Italy. > Department of Epidemiology, Preclinical Research and Advanced Diagnostics
Refolo, Giulia; National Institute for Infectious Diseases Irccs "L. Spallanzani", Rome, Italy > Department of Epidemiology, Preclinical Research and Advanced Diagnostics
Consalvi, Veronica; University of Rome "Sapienza", Rome, Italy > Department of Molecular Medicine
ARENA, Giuseppe ; University of Luxembourg > Luxembourg Centre for Systems Biomedicine (LCSB) > Translational Neuroscience
Valente, Enza Maria; University of Pavia, Pavia, Italy > Department of Molecular Medicine
Piacentini, Mauro; National Institute for Infectious Diseases Irccs "L. Spallanzani", Rome, Italy > Department of Epidemiology, Preclinical Research and Advanced Diagnostics
Fimia, Gian Maria; National Institute for Infectious Diseases Irccs "L. Spallanzani", Rome, Italy > Department of Epidemiology, Preclinical Research and Advanced Diagnostics
Co-auteurs externes :
yes
Langue du document :
Anglais
Titre :
AMBRA1 regulates mitophagy by interacting with ATAD3A and promoting PINK1 stability
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