Respiratory complex and tissue lineage drive recurrent mutations in tumour mtDNA.

ABSTRACT: Mitochondrial DNA (mtDNA) encodes protein subunits and translational machinery required for oxidative phosphorylation (OXPHOS). Using repurposed whole-exome sequencing data, in the present study we demonstrate that pathogenic mtDNA mutations arise in tumours at a rate comparable to those in the most common cancer driver genes. We identify OXPHOS complexes as critical determinants shaping somatic mtDNA mutation patterns across tumour lineages. Loss-of-function mutations accumulate at an elevated rate specifically in complex I and often arise at specific homopolymeric hotspots. In contrast, complex V is depleted of all non-synonymous mutations, suggesting that impairment of ATP synthesis and mitochondrial membrane potential dissipation are under negative selection. Common truncating mutation

SUBMITTER: Gorelick AN 

PROVIDER: S-EPMC9304985 | biostudies-literature | 2021 Apr

REPOSITORIES: biostudies-literature