Ubiquitin-mediated mitophagy regulates the inheritance of mitochondrial DNA mutations
OA Location
Author(s)
Type
Journal Article
Abstract
Mitochondrial synthesis of ATP is essential for eukaryotic life but is dependent on the co-operation of two genomes: nuclear and mitochondrial DNA (mtDNA). MtDNA mutates ~15-fold faster than the nuclear genome, challenging this symbiotic relationship. Mechanisms must have evolved to moderate the impact of mtDNA mutagenesis, but are poorly understood. Here, we observed purifying selection of a murine mtDNA mutation modulated by Ubiquitin-specific Peptidase 30 (Usp30) during the maternal-zygotic transition. In vitro, Usp30 inhibition recapitulated these findings by increasing ubiquitin-mediated mitochondrial autophagy (mitophagy). We also found that high mutant burden, or heteroplasmy, impairs the ubiquitin proteasome system, explaining how mutations can evade quality control to cause disease. Inhibiting USP30 unleashes latent mitophagy, reducing mutant mtDNA in high-heteroplasmy cells. These findings suggest a potential strategy to prevent mitochondrial disorders.
Date Acceptance
2025-07-17
Citation
Science
ISSN
0036-8075
Publisher
American Association for the Advancement of Science
Journal / Book Title
Science
Copyright Statement
Subject to copyright.
Publication Status
Accepted