Eukaryotic metabolism relies on the cooperation between two genomes: nuclear and mitochondrial DNA (mtDNA). Mitophagy, the selective autophagic removal of mitochondria, is a central quality-control axis that determines mtDNA’s fate. Michele Frison established mtDNA as a substrate of this surveillance system: They showed that ubiquitin-mediated mitophagy governs the inheritance of mtDNA mutations, that a high mutant burden cripples the ubiquitin–proteasome system to let mutations evade clearance, and that inhibiting USP30 restores mitophagy to purge mutant mtDNA (1). The group is now bringing this framework to oncology, where roughly half of all tumours carry somatic mtDNA mutations, and where, in certain cancers, pathogenic mtDNA variants recur at rates comparable to common nuclear driver genes (2,3). Because these mutations arise somatically and are rarely inherited, they are confined to the tumour itself. The group of Michele Frison now investigates how mtDNA-mutant cancers exploit, and escape, ubiquitin-mediated quality control, with the aim of turning this tumour-restricted mutant burden into a selective vulnerability.

References
(1) Frison, M. et al. Ubiquitin-mediated mitophagy regulates the inheritance of mitochondrial DNA mutations. Science 390, 156–163 (2025).
(2) Boscenco, S. et al. Functionally dominant hotspot mutations of mitochondrial ribosomal RNA genes in cancer. Nat Genet 57, 2705–2714 (2025).
(3) Kim, M., Mahmood, M., Reznik, E. & Gammage, P. A. Mitochondrial DNA is a major source of driver mutations in cancer. Trends in Cancer 8, 1046–1059 (2022).