Strappazzon F, Nazio F, Corrado M, Cianfanelli V, Romagnoli A, Fimia G M, Campello S, Nardacci R, Piacentini M, Campanella M, Cecconi F
1] IRCCS Fondazione Santa Lucia, Rome, Italy [2] Department of Biology, University of Rome Tor Vergata, Rome, Italy.
IRCCS Fondazione Santa Lucia, Rome, Italy.
Cell Death Differ. 2015 Mar;22(3):419-32. doi: 10.1038/cdd.2014.139. Epub 2014 Sep 12.
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.
受损的线粒体通过线粒体自噬被清除，线粒体自噬是一种选择性自噬形式，其功能障碍与神经退行性疾病相关。已有研究表明，PINK1、PARKIN和p62/SQSTM1可调节线粒体自噬，而“一般”自噬中的关键参与者所起的作用迄今仍不明确。在基础条件下，AMBRA1（一种上游自噬调节因子和PARKIN相互作用蛋白）的一部分存在于线粒体中，其促自噬活性受到Bcl-2的抑制。我们在此表明，在线粒体自噬诱导后，AMBRA1通过一个LIR（LC3相互作用区域）基序与自噬体衔接蛋白LC3结合，这种相互作用对于调节经典的PARKIN依赖性和非依赖性线粒体清除至关重要。此外，迫使AMBRA1定位于线粒体外膜会引发大量不依赖PARKIN和p62但依赖LC3的线粒体自噬。这些结果突出了AMBRA1作为一种强大的线粒体自噬调节因子的新作用，其通过经典或非经典途径发挥作用。
