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Title: Endosomal Rab cycles regulate Parkin-mediated mitophagy
Authors: Yamano, Koji
Wang, Chunxin
Sarraf, Shireen A
Münch, Chiristian
Kikuchi, Reika
Noda, Nobuo N
Hizukuri, Yohei  kyouindb  KAKEN_id
Kanemaki, Masato T
Harper, Wade
Tanaka, Keiji
Matsuda, Noriyuki
Youle, Richard J
Author's alias: 檜作, 洋平
Keywords: RESEARCH ARTICLE
CELL BIOLOGY
MITOCHONDRIA
AUTOPHAGY
PARKIN
UBIQUITIN
RAB7
Issue Date: 23-Jan-2018
Publisher: eLife Sciences Organisation, Ltd.
Journal title: eLife
Volume: 7
Thesis number: e31326
Abstract: 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.
Rights: 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.
URI: http://hdl.handle.net/2433/230629
DOI(Published Version): 10.7554/eLife.31326
PubMed ID: 29360040
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