Endosomal Rab cycles regulate Parkin-mediated mitophagy

  • 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.
Metadaten
Author:Koji Yamano, Chunxin Wang, Shireen A. Sarraf, Christian Münch, Reika Kikuchi, Nobuo N. Noda, Yohei Hizukuri, Masato T. Kanemaki, Wade Harper, Keiji Tanaka, Noriyuki Matsuda, Richard J. Youle
URN:urn:nbn:de:hebis:30:3-477327
DOI:https://doi.org/10.7554/eLife.31326.001
ISSN:2050-084X
Pubmed Id:https://pubmed.ncbi.nlm.nih.gov/29360040
Parent Title (English):eLife
Publisher:eLife Sciences Publications
Place of publication:Cambridge
Contributor(s):Ivan Đikić
Document Type:Article
Language:English
Year of Completion:2018
Date of first Publication:2018/01/23
Publishing Institution:Universitätsbibliothek Johann Christian Senckenberg
Release Date:2018/10/25
Tag:Parkin; Rab7; Research article; autophagy; cell biology; human; mitochondria; ubiquitin
Volume:7
Issue:e31326
Page Number:32
First Page:1
Last Page:32
Note:
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.
HeBIS-PPN:439098335
Institutes:Medizin / Medizin
Dewey Decimal Classification:6 Technik, Medizin, angewandte Wissenschaften / 61 Medizin und Gesundheit / 610 Medizin und Gesundheit
Sammlungen:Universitätspublikationen
Licence (German):License LogoCreative Commons - Namensnennung 4.0