Ubiquitin-mediated mitophagy regulates the inheritance of mitochondrial DNA mutations.

Mitochondrial synthesis of adenosine triphosphate is essential for eukaryotic life but is dependent on the cooperation of two genomes: nuclear and mitochondrial DNA (mtDNA). mtDNA mutates ~15 times as fast as 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 mouse 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. Editor's summary: Mitochondrial production of adenosine triphosphate (ATP) is essential for life and depends on the cooperation of mitochondrial DNA (mtDNA) with the nuclear genome, but little is known about the mechanisms ensuring nuclear-mtDNA compatibility. Frison et al. found that mitochondria harboring a mtDNA mutation evade mitochondrial quality control by inhibiting the ubiquitin proteasome system. In mouse models, restoring mitochondrial ubiquitination through ubiquitin-specific peptidase 30 (Usp30) loss increased purifying selection of mtDNA in early embryogenesis. In vitro, genetically or chemically inhibiting Usp30 reduced mutant burden by increasing ubiquitin-mediated mitochondrial autophagy. Usp30 thus provides a promising target to treat and prevent mtDNA disorders. —Stella M. Hurtley [ABSTRACT FROM AUTHOR]