RRC ID 76841
Author Sanchez-Martinez A, Martinez A, Whitworth AJ.
Title FBXO7/ntc and USP30 antagonistically set the ubiquitination threshold for basal mitophagy and provide a target for Pink1 phosphorylation in vivo.
Journal PLoS Biol
Abstract Functional analyses of genes linked to heritable forms of Parkinson's disease (PD) 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 that triggers stress-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.
Volume 21(8)
Pages e3002244
Published 2023-8-1
DOI 10.1371/journal.pbio.3002244
PMID 37535686
PMC PMC10427020
MeSH Animals Drosophila / metabolism Mitophagy / genetics Parkinson Disease* / metabolism Parkinson Disease, Secondary* Phosphorylation Ubiquitin-Protein Ligases / genetics Ubiquitin-Protein Ligases / metabolism Ubiquitination
IF 7.076
Drosophila 3016R-2