Compensatory upregulation of respiratory chain complexes III and IV in isolated deficiency of ATP synthase due to TMEM70 mutation

Biochim Biophys Acta. 2012 Jul;1817(7):1037-43. doi: 10.1016/j.bbabio.2012.03.004. Epub 2012 Mar 10.


Early onset mitochondrial encephalo-cardiomyopathy due to isolated deficiency of ATP synthase is frequently caused by mutations in TMEM70 gene encoding enzyme-specific ancillary factor. Diminished ATP synthase results in low ATP production, elevated mitochondrial membrane potential and increased ROS production. To test whether the patient cells may react to metabolic disbalance by changes in oxidative phosphorylation system, we performed a quantitative analysis of respiratory chain complexes and intramitochondrial proteases involved in their turnover. SDS- and BN-PAGE Western blot analysis of fibroblasts from 10 patients with TMEM70 317-2A>G homozygous mutation showed a significant 82-89% decrease of ATP synthase and 50-162% increase of respiratory chain complex IV and 22-53% increase of complex III. The content of Lon protease, paraplegin and prohibitins 1 and 2 was not significantly changed. Whole genome expression profiling revealed a generalized upregulation of transcriptional activity, but did not show any consistent changes in mRNA levels of structural subunits, specific assembly factors of respiratory chain complexes, or in regulatory genes of mitochondrial biogenesis which would parallel the protein data. The mtDNA content in patient cells was also not changed. The results indicate involvement of posttranscriptional events in the adaptive regulation of mitochondrial biogenesis that allows for the compensatory increase of respiratory chain complexes III and IV in response to deficiency of ATP synthase.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • DNA, Mitochondrial / metabolism
  • Electron Transport / genetics
  • Electron Transport Complex III / metabolism*
  • Electron Transport Complex IV / metabolism*
  • Fibroblasts / metabolism
  • Fibroblasts / pathology
  • Gene Expression Profiling
  • Humans
  • Membrane Proteins / genetics*
  • Mitochondria / enzymology
  • Mitochondria / genetics
  • Mitochondrial Proteins / genetics*
  • Mitochondrial Proton-Translocating ATPases / deficiency*
  • Mitochondrial Proton-Translocating ATPases / metabolism
  • Mutation / genetics*
  • Oxidative Phosphorylation
  • Peptide Hydrolases / metabolism
  • RNA, Messenger / genetics
  • RNA, Messenger / metabolism
  • Up-Regulation*


  • DNA, Mitochondrial
  • Membrane Proteins
  • Mitochondrial Proteins
  • RNA, Messenger
  • TMEM70 protein, human
  • Electron Transport Complex IV
  • Peptide Hydrolases
  • Mitochondrial Proton-Translocating ATPases
  • Electron Transport Complex III