Skeletal muscle mitochondria of NDUFS4-/- mice display normal maximal pyruvate oxidation and ATP production

Research output: Contribution to journalArticle

Authors

  • Mohammad T Alam
  • Ganesh Manjeri
  • Jan A M Smeitink
  • Richard A Notebaart
  • Martijn Huynen

Colleges, School and Institutes

Abstract

Mitochondrial ATP production is mediated by the oxidative phosphorylation (OXPHOS) system, which consists of four multi-subunit complexes (CI-CIV) and the FoF1-ATP synthase (CV). Mitochondrial disorders including Leigh Syndrome often involve CI dysfunction, the pathophysiological consequences of which still remain incompletely understood. Here we combined experimental and computational strategies to gain mechanistic insight into the energy metabolism of isolated skeletal muscle mitochondria from 5-week-old wild-type (WT) and CI-deficient NDUFS4-/- (KO) mice. Enzyme activity measurements in KO mitochondria revealed a reduction of 79% in maximal CI activity (Vmax), which was paralleled by 45-72% increase in Vmax of CII, CIII, CIV and citrate synthase. Mathematical modeling of mitochondrial metabolism predicted that these Vmax changes do not affect the maximal rates of pyruvate (PYR) oxidation and ATP production in KO mitochondria. This prediction was empirically confirmed by flux measurements. In silico analysis further predicted that CI deficiency altered the concentration of intermediate metabolites, modestly increased mitochondrial NADH/NAD+ ratio and stimulated the lower half of the TCA cycle, including CII. Several of the predicted changes were previously observed in experimental models of CI-deficiency. Interestingly, model predictions further suggested that CI deficiency only has major metabolic consequences when its activity decreases below 90% of normal levels, compatible with a biochemical threshold effect. Taken together, our results suggest that mouse skeletal muscle mitochondria possess a substantial CI overcapacity, which minimizes the effects of CI dysfunction on mitochondrial metabolism in this otherwise early fatal mouse model.

Details

Original languageEnglish
Pages (from-to)526-33
Number of pages8
JournalBiochimica et Biophysica Acta
Volume1847
Issue number6-7
Publication statusPublished - 18 Feb 2015

Keywords

  • Adenosine Triphosphate, Animals, Computational Biology, Electron Transport Complex I, Energy Metabolism, Leigh Disease, Mice, Mice, Inbred C57BL, Mice, Knockout, Mitochondria, Muscle, Models, Theoretical, Muscle, Skeletal, Oxidation-Reduction, Oxidative Phosphorylation, Oxygen Consumption, Pyruvates