期刊
CELL DEATH AND DIFFERENTIATION
卷 22, 期 3, 页码 419-432出版社
NATURE PUBLISHING GROUP
DOI: 10.1038/cdd.2014.139
关键词
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资金
- Telethon Italy [GTB12001]
- Telethon Foundation [GGP10225]
- AIRC
- FISM
- Italian Ministry of University and Research
- Italian Ministry of Health [RF-OGR-2008-120-3614]
- Biotechnology and Biological Sciences Research Council [BB/I013695/1] Funding Source: researchfish
- Lundbeck Foundation [R165-2013-15982] Funding Source: researchfish
- BBSRC [BB/I013695/1] Funding Source: UKRI
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.
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