The Parkinson's disease-linked proteins Fbxo7 and Parkin interact to mediate mitophagy.
Burchell, Victoria S
Ivatt, Rachael M
Pogson, Joe H
Randle, Suzanne J
Lewis, Patrick A
Abramov, Andrey Y
Wood, Nicholas W
Nature Publishing Group
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Burchell, V. S., Nelson, D., Sanchez-Martinez, A., Delgado-Camprubi, M., Ivatt, R. M., Pogson, J. H., Randle, S. J., et al. (2013). The Parkinson's disease-linked proteins Fbxo7 and Parkin interact to mediate mitophagy.. Nature Neuroscience, 16 (9), 1257-1265. https://doi.org/10.1038/nn.3489
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.
Animals, 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
European Commission FP7 ERC Starting Independent Researcher Grant (SIRG) (309742)
External DOI: https://doi.org/10.1038/nn.3489
This record's URL: https://www.repository.cam.ac.uk/handle/1810/266030