Liu Lei, Sakakibara Kaori, Chen Quan, Okamoto Koji
State Key Laboratory of Biomembrane and Membrane Biotechnology, Institute of Zoology, Chinese Academy of Sciences, Beijing 100101, China.
Laboratory of Mitochondrial Dynamics, Graduate School of Frontier Biosciences, Osaka University, Suita, Osaka 565-0871, Japan.
Cell Res. 2014 Jul;24(7):787-95. doi: 10.1038/cr.2014.75. Epub 2014 Jun 6.
Mitophagy, or mitochondria autophagy, plays a critical role in selective removal of damaged or unwanted mitochondria. Several protein receptors, including Atg32 in yeast, NIX/BNIP3L, BNIP3 and FUNDC1 in mammalian systems, directly act in mitophagy. Atg32 interacts with Atg8 and Atg11 on the surface of mitochondria, promoting core Atg protein assembly for mitophagy. NIX/BNIP3L, BNIP3 and FUNDC1 also have a classic motif to directly bind LC3 (Atg8 homolog in mammals) for activation of mitophagy. Recent studies have shown that receptor-mediated mitophagy is regulated by reversible protein phosphorylation. Casein kinase 2 (CK2) phosphorylates Atg32 and activates mitophagy in yeast. In contrast, in mammalian cells Src kinase and CK2 phosphorylate FUNDC1 to prevent mitophagy. Notably, in response to hypoxia and FCCP treatment, the mitochondrial phosphatase PGAM5 dephosphorylates FUNDC1 to activate mitophagy. Here, we mainly focus on recent advances in our understanding of the molecular mechanisms underlying the activation of receptor-mediated mitophagy and the implications of this catabolic process in health and disease.
线粒体自噬，即线粒体的自噬作用，在选择性清除受损或不需要的线粒体方面发挥着关键作用。几种蛋白质受体，包括酵母中的Atg32、哺乳动物系统中的NIX/BNIP3L、BNIP3和FUNDC1，直接参与线粒体自噬。Atg32在线粒体表面与Atg8和Atg11相互作用，促进线粒体自噬核心Atg蛋白的组装。NIX/BNIP3L、BNIP3和FUNDC1也有一个经典基序，可直接结合LC3（哺乳动物中的Atg8同源物）以激活线粒体自噬。最近的研究表明，受体介导的线粒体自噬受可逆蛋白磷酸化的调节。酪蛋白激酶2（CK2）使Atg32磷酸化并激活酵母中的线粒体自噬。相反，在哺乳动物细胞中，Src激酶和CK2使FUNDC1磷酸化以阻止线粒体自噬。值得注意的是，在缺氧和FCCP处理的情况下，线粒体磷酸酶PGAM5使FUNDC1去磷酸化以激活线粒体自噬。在此，我们主要关注我们对受体介导的线粒体自噬激活的分子机制的最新理解进展，以及这一分解代谢过程在健康和疾病中的意义。
