The Parkinson's disease-linked proteins Fbxo7 and Parkin interact to mediate mitophagy.

TitleThe Parkinson's disease-linked proteins Fbxo7 and Parkin interact to mediate mitophagy.
Publication TypeJournal Article
Year of Publication2013
AuthorsBurchell, VS, Nelson, DE, Sanchez-Martinez, A, Delgado-Camprubi, M, Ivatt, RM, Pogson, JH, Randle, SJ, Wray, S, Lewis, PA, Houlden, H, Abramov, AY, Hardy, J, Wood, NW, Whitworth, AJ, Laman, H, Plun-Favreau, H
JournalNat Neurosci
Volume16
Issue9
Pagination1257-65
Date Published2013 Sep
ISSN1546-1726
KeywordsAnimals, Animals, Genetically Modified, Carbonyl Cyanide m-Chlorophenyl Hydrazone, Cell Line, Tumor, Cells, Cultured, Drosophila, F-Box Proteins, Female, Fertility, Fibroblasts, Humans, Male, Microtubule-Associated Proteins, Mitochondria, Mitochondrial Degradation, Mutation, Parkinson Disease, Protein Transport, Proton Ionophores, RNA, Small Interfering, Time Factors, Ubiquitin-Protein Ligases, Ubiquitination
Abstract

Compelling evidence indicates that two autosomal recessive Parkinson's disease genes, PINK1 (PARK6) and Parkin (PARK2), cooperate to mediate the autophagic clearance of damaged mitochondria (mitophagy). Mutations in the F-box domain-containing protein Fbxo7 (encoded by PARK15) also cause early-onset autosomal recessive Parkinson's disease, by an unknown mechanism. Here we show that Fbxo7 participates in mitochondrial maintenance through direct interaction with PINK1 and Parkin and acts in Parkin-mediated mitophagy. Cells with reduced Fbxo7 expression showed deficiencies in translocation of Parkin to mitochondria, ubiquitination of mitofusin 1 and mitophagy. In Drosophila, ectopic overexpression of Fbxo7 rescued loss of Parkin, supporting a functional relationship between the two proteins. Parkinson's disease-causing mutations in Fbxo7 interfered with this process, emphasizing the importance of mitochondrial dysfunction in Parkinson's disease pathogenesis.

DOI10.1038/nn.3489
Alternate JournalNat. Neurosci.
Citation Key10.1038/nn.3489
PubMed ID23933751
PubMed Central IDPMC3827746
Grant List089698 / / Wellcome Trust / United Kingdom
309742 / / European Research Council / International
BB/F012764/1 / / Biotechnology and Biological Sciences Research Council / United Kingdom
BB/F012764/1 / / Biotechnology and Biological Sciences Research Council / United Kingdom
BB/J007846/1 / / Biotechnology and Biological Sciences Research Council / United Kingdom
F-1002 / / Parkinson's UK / United Kingdom
G0700183 / / Medical Research Council / United Kingdom
G0700183 / / Medical Research Council / United Kingdom
G070091 / / Medical Research Council / United Kingdom
G0701075 / / Medical Research Council / United Kingdom
G0802760 / / Medical Research Council / United Kingdom
GR077544AIA / / Wellcome Trust / United Kingdom
H-1006 / / Parkinson's UK / United Kingdom
MC_G1000735 / / Medical Research Council / United Kingdom
WT089698 / / Wellcome Trust / United Kingdom