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FBXO7/ntc and USP30 antagonistically set the ubiquitination threshold for basal mitophagy and provide a target for Pink1 phosphorylation in vivo

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Sanchez-Martinez, Alvaro 
Whitworth, Alexander 
Martinez, Aitor 


Functional analyses of genes linked to heritable forms of Parkinson's disease have revealed fundamental insights into the biological processes underpinning pathogenic mechanisms. Mutations in PARK15/FBXO7 cause autosomal recessive PD and FBXO7 has been shown to regulate mitochondrial homeostasis. We investigated the extent to which FBXO7 and its Drosophila orthologue, ntc, share functional homology and explored its role in mitophagy in vivo. We show that ntc mutants partially phenocopy Pink1 and parkin mutants and ntc overexpression supresses parkin phenotypes. Furthermore, ntc can modulate basal mitophagy in a Pink1- and parkin- independent manner by promoting the ubiquitination of mitochondrial proteins, a mechanism that is opposed by the deubiquitinase USP30. This basal ubiquitination serves as the substrate for Pink1-mediated phosphorylation which triggers damage- induced mitophagy. We propose that FBXO7/ntc works in equilibrium with USP30 to provide a checkpoint for mitochondrial quality control in basal conditions in vivo and presents a new avenue for therapeutic approaches.


Acknowledgements: We kindly thank Herman Steller for generously sharing the ntc lines, Ugo Mayor for the USP30 overexpression lines, and Ian Ganley for the ARPE-19-MQC cells. We thank Roberta Tufi for performing the ATP assay, Wing Hei Au and Federica De Lazzari for comments and edits on the manuscript, and all the members of the Whitworth’s lab for discussions. Stocks were obtained from the Bloomington Drosophila Stock Center which is supported by grant NIH P40OD018537.


Animals, Phosphorylation, Mitophagy, Ubiquitination, Ubiquitin-Protein Ligases, Parkinson Disease, Secondary, Parkinson Disease, Drosophila

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PLoS Biology

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Public Library of Science (PLoS)
MRC (MC_UU_00028/6)