TY  - JOUR
A1  - Yamano, Koji
A1  - Wang, Chunxin
A1  - Sarraf, Shireen A.
A1  - Münch, Christian
A1  - Kikuchi, Reika
A1  - Noda, Nobuo N.
A1  - Hizukuri, Yohei
A1  - Kanemaki, Masato T.
A1  - Harper, Wade
A1  - Tanaka, Keiji
A1  - Matsuda, Noriyuki
A1  - Youle, Richard J.
T1  - Endosomal Rab cycles regulate Parkin-mediated mitophagy
T2  - eLife
N2  - 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.
KW  - Research article
KW  - cell biology
KW  - mitochondria
KW  - autophagy
KW  - Parkin
KW  - ubiquitin
KW  - Rab7
KW  - human
Y1  - 2018
UR  - http://publikationen.ub.uni-frankfurt.de/frontdoor/index/index/docId/47732
UR  - https://nbn-resolving.org/urn:nbn:de:hebis:30:3-477327
SN  - 2050-084X
N1  - Copyright Yamano et al. This article is distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use and redistribution provided that the original author and source are credited.
VL  - 7
IS  - e31326
SP  - 1
EP  - 32
PB  - eLife Sciences Publications
CY  - Cambridge
ER  -