Homoplasmic deleterious MT-ATP6/8 mutations in adult patients

Mitochondrion. 2020 Nov:55:64-77. doi: 10.1016/j.mito.2020.08.004. Epub 2020 Aug 26.


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.

Keywords: ATP synthase; Cybrids; Homoplasmy; Mitochondrial DNA; Mitochondrial disease; Oxidative phosphorylation.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adult
  • Cells, Cultured
  • Female
  • Fibroblasts / chemistry
  • Fibroblasts / cytology
  • High-Throughput Nucleotide Sequencing
  • Humans
  • Hybrid Cells / chemistry
  • Hybrid Cells / cytology
  • Male
  • Mitochondrial Diseases / genetics*
  • Mitochondrial Proton-Translocating ATPases / genetics*
  • Muscle, Skeletal / chemistry
  • Muscle, Skeletal / cytology
  • Mutation
  • Oxidative Phosphorylation
  • Polymorphism, Single Nucleotide*
  • Sequence Analysis, DNA


  • MT-ATP6 protein, human
  • MT-ATP8 protein, human
  • Mitochondrial Proton-Translocating ATPases