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Nat Neurosci. 2013 Sep;16(9):1257-65. doi: 10.1038/nn.3489. Epub 2013 Aug 11.

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

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1
Department of Molecular Neuroscience, University College London Institute of Neurology, London, UK.

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.

PMID:
23933751
PMCID:
PMC3827746
DOI:
10.1038/nn.3489
[Indexed for MEDLINE]
Free PMC Article

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