FBXO7/ntc and USP30 antagonistically set the basal ubiquitination threshold for mitophagy

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 orthologue in Drosophila 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 mitophagy in a Pink1- and parkin-independent manner by promoting the ubiquitination of OMM 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. ### Competing Interest Statement The authors have declared no competing interest.