eLife | |
Endosomal Rab cycles regulate Parkin-mediated mitophagy | |
Chunxin Wang1  Noriyuki Matsuda2  Richard J Youle3  Nobuo N Noda4  Christian Münch5  Shireen A Sarraf5  Reika Kikuchi6  Keiji Tanaka7  Wade Harper8  Masato T Kanemaki9  Koji Yamano1,10  Yohei Hizukuri1,10  | |
[1] Biochemistry Section, Surgical Neurology Branch, National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, United States;Department of Genetics, SOKENDAI, Mishima, Japan;Division of Molecular Cell Engineering, National Institute of Genetics, ROIS, Mishima, Japan;Institute of Biochemistry II, School of Medicine, Goethe University, Frankfurt, Germany;Biochemistry Section, Surgical Neurology Branch, National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, United States;Department of Cell Biology, Harvard Medical School, Boston, United States;Division of Molecular Cell Engineering, National Institute of Genetics, Research Organization of Information and Systems, Mishima, Japan;Institute for Frontier Life and Medical Sciences, Kyoto University, Kyoto, Japan;Institute of Microbial Chemistry, Tokyo, Japan;Ubiquitin Project, Tokyo Metropolitan Institute of Medical Science, Tokyo, Japan; | |
关键词: mitochondria; autophagy; Parkin; ubiquitin; Rab7; | |
DOI : 10.7554/eLife.31326 | |
来源: DOAJ |
【 摘 要 】
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.
【 授权许可】
Unknown