Reference : AMBRA1 regulates mitophagy by interacting with ATAD3A and promoting PINK1 stability

	Document type :	Scientific journals : Article
	Discipline(s) :	Human health sciences : Multidisciplinary, general & others
	Focus Areas :	Systems Biomedicine
	To cite this reference:	http://hdl.handle.net/10993/54771

Title :	AMBRA1 regulates mitophagy by interacting with ATAD3A and promoting PINK1 stability
Language :	English
Author, co-author :	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]
Publication date :	Aug-2022
Journal title :	Autophagy
Publisher :	Landes Bioscience
Volume :	18
Issue/season :	8
Pages :	1752-1762
Peer reviewed :	Yes
Audience :	International
ISSN :	1554-8627
e-ISSN :	1554-8635
City :	Georgetown
Country :	United States - Texas
Keywords :	[en] PINK1 ; Autophagy ; AMBRA1
Abstract :	[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.
Target :	Researchers ; Professionals ; Students ; General public
Permalink :	http://hdl.handle.net/10993/54771
DOI :	10.1080/15548627.2021.1997052
FnR project :	FnR ; FNR11676395 > Rejko Krüger > MiRisk-PD > Mitochondrial Risk Factors In Parkinson's Disease > 01/03/2018 > 31/08/2021 > 2017

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