The Parkinson's disease-linked proteins Fbxo7 and Parkin interact to mediate mitophagy.
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.
Department of Molecular Neuroscience, University College London Institute of Neurology, London, UK.
Victoria S
VS
Burchell
David E
DE
Nelson
Alvaro
A
Sanchez-Martinez
Marta
M
Delgado-Camprubi
Rachael M
RM
Ivatt
Joe H
JH
Pogson
Suzanne J
SJ
Randle
Selina
S
Wray
Patrick A
PA
Lewis
Henry
H
Houlden
Andrey Y
AY
Abramov
John
J
Hardy
Nicholas W
NW
Wood
Alexander J
AJ
Whitworth
Heike
H
Laman
Helene
H
Plun-Favreau
D000818:Animals; D030801:Animals, Genetically Modified; D002258:Carbonyl Cyanide m-Chlorophenyl Hydrazone / Q000494:pharmacology; D045744:Cell Line, Tumor; D002478:Cells, Cultured; D004330:Drosophila; D044783:F-Box Proteins / Q000235:genetics / Q000378:metabolism*; D005260:Female; D005298:Fertility / Q000235:genetics; D005347:Fibroblasts / Q000187:drug effects / Q000473:pathology / Q000648:ultrastructure; D006801:Humans; D008297:Male; D008869:Microtubule-Associated Proteins / Q000378:metabolism; D008928:Mitochondria / Q000473:pathology; D063306:Mitophagy / Q000187:drug effects / Q000235:genetics*; D009154:Mutation / Q000235:genetics; D010300:Parkinson Disease / Q000235:genetics* / Q000473:pathology; D021381:Protein Transport / Q000187:drug effects / Q000235:genetics; D061209:Proton Ionophores / Q000494:pharmacology; D034741:RNA, Small Interfering / Q000235:genetics / Q000378:metabolism; D013997:Time Factors; D044767:Ubiquitin-Protein Ligases / Q000235:genetics / Q000378:metabolism*; D054875:Ubiquitination / Q000187:drug effects / Q000235:genetics
D044783:F-Box Proteins; C489149:FBXO7 protein, human; C477012:MAP1LC3A protein, human; D008869:Microtubule-Associated Proteins; D061209:Proton Ionophores; D034741:RNA, Small Interfering; D002258:Carbonyl Cyanide m-Chlorophenyl Hydrazone; D044767:Ubiquitin-Protein Ligases; C111567:parkin protein