Homoplasmic deleterious MT-ATP6/8 mutations in adult patients

[Display omitted] •Numerous homoplasmic MT-ATP6/8 missense mutations are potentially deleterious (putative) mutations.•Functional analyses disclose striking gradation in severity and tissue-specific expression.•Efficient compensation of deleterious MT-ATP6/8 mutations appears common.•Under-diagnosis of human complex V defect is a likely hypothesis.•With respect to diagnosis, fibroblasts are most often non informative. To address the frequency of complex V defects, we systematically sequenced MT-ATP6/8 genes in 512 consecutive patients. We performed functional analysis in muscle or fibroblasts for 12 out of 27 putative homoplasmic mutations and in cybrids for four. Fibroblasts, muscle and cybrids with known deleterious mutations underwent parallel analysis. It included oxidative phosphorylation spectrophotometric assays, western blots, structural analysis, ATP production, glycolysis and cell proliferation evaluation. We demonstrated the deleterious nature of three original mutations. Striking gradation in severity of the mutations consequences and differences between muscle, fibroblasts and cybrids implied a likely under-diagnosis of human complex V defects.