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 <i>Ubiquitin-specific peptidase 30</i> (<i>Usp30</i>) during the maternal-zygotic transition. In vitro, <i>Usp30</i> 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.

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Publication Details

Journal
Science
Published
2025-10-09
DOI
https://doi.org/10.1126/science.adr5438
Citations
5
Primary Topic
Autophagy in Disease and Therapy
Type
article
Field-Weighted Citation Impact
6.77
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Ubiquitin-mediated mitophagy regulates the inheritance of mitochondrial DNA mutations

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Ubiquitin-mediated mitophagy regulates the inheritance of mitochondrial DNA mutations

Lyuba V. Bozhilova, Patrick Francis Chinnery, Angelos Glynos, James B. Stewart, Nick S. Jones, Zoe Golder, Stephen P. Burr, Marcos Roberto Chiaratti, Cameron Ryall, Yu Nie, Michele Frison, Malwina Prater, C J Lyons, Brandon S. Lockey, Eleni Theiaspra
article en
5 citations

Abstract

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 <i>Ubiquitin-specific peptidase 30</i> (<i>Usp30</i>) during the maternal-zygotic transition. In vitro, <i>Usp30</i> 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.

ScienceVol. 390(6769)
Universidade Federal de São Carlos (BR), University of Cambridge (GB), Imperial College London (GB), MRC Mitochondrial Biology Unit (GB), Newcastle University (GB), Medical Research Council (GB)
Openalex Percentile: Top 3%
Autophagy in Disease and Therapy
6.77
DOISourceOpenAlex
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