Endosomal Rab cycles regulate Parkin-mediated mitophagy.
Endosomal Rab cycles regulate Parkin-mediated mitophagy.
复制标题
内体RAB循环调节Parkin介导的线粒体。
DOI：
10.7554/elife.31326
复制
发表时间：
2018-01-23
期刊：
影响因子：
7.7
通讯作者：
Youle RJ
中科院分区：
文献类型：
--
作者：
Yamano K;Wang C;Sarraf SA;Münch C;Kikuchi R;Noda NN;Hizukuri Y;Kanemaki MT;Harper W;Tanaka K;Matsuda N;Youle RJ
Damaged mitochondria are selectively eliminated by mitophagy. Parkin and PINK1, gene products mutated in familial Parkinson’s disease, play essential roles in mitophagy through ubiquitination of mitochondria. Cargo ubiquitination by E3 ubiquitin ligase Parkin is important to trigger selective autophagy. Although autophagy receptors recruit LC3-labeled autophagic membranes onto damaged mitochondria, how other essential autophagy units such as ATG9A-integrated vesicles are recruited remains unclear. Here, using mammalian cultured cells, we demonstrate that RABGEF1, the upstream factor of the endosomal Rab GTPase cascade, is recruited to damaged mitochondria via ubiquitin binding downstream of Parkin. RABGEF1 directs the downstream Rab proteins, RAB5 and RAB7A, to damaged mitochondria, whose associations are further regulated by mitochondrial Rab-GAPs. Furthermore, depletion of RAB7A inhibited ATG9A vesicle assembly and subsequent encapsulation of the mitochondria by autophagic membranes. These results strongly suggest that endosomal Rab cycles on damaged mitochondria are a crucial regulator of mitophagy through assembling ATG9A vesicles.
