title: Skeletal muscle mitochondria of NDUFS4-/- mice display normal maximal pyruvate oxidation and ATP production.
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.
authors: Department of Biochemistry, RIMLS, Radboud University Medical Center, Nijmegen, The Netherlands; Centre for Systems Biology and Bioenergetics, Radboud University Medical Centre, Nijmegen, The Netherlands. Electronic address: mta26@cam.ac.uk.
authors: Mohammad T
authors: MT
authors: Alam
authors: Department of Biochemistry, RIMLS, Radboud University Medical Center, Nijmegen, The Netherlands; Centre for Systems Biology and Bioenergetics, Radboud University Medical Centre, Nijmegen, The Netherlands. Electronic address: Ganesh.Manjeri@radboudumc.nl.
authors: Ganesh R
authors: GR
authors: Manjeri
authors: Centre for Systems Biology and Bioenergetics, Radboud University Medical Centre, Nijmegen, The Netherlands; Department of Pediatrics, NCMD, Radboud University Medical Center, Nijmegen, The Netherlands. Electronic address: Richard.Rodenburg@radboudumc.nl.
authors: Richard J
authors: RJ
authors: Rodenburg
authors: Centre for Systems Biology and Bioenergetics, Radboud University Medical Centre, Nijmegen, The Netherlands; Department of Pediatrics, NCMD, Radboud University Medical Center, Nijmegen, The Netherlands. Electronic address: Jan.Smeitink@radboudumc.nl.
authors: Jan A M
authors: JA
authors: Smeitink
authors: Centre for Systems Biology and Bioenergetics, Radboud University Medical Centre, Nijmegen, The Netherlands; Centre for Molecular and Biomolecular Informatics, RIMLS, Radboud University Medical Center, Nijmegen, The Netherlands. Electronic address: Richard.Notebaart@radboudumc.nl.
authors: Richard A
authors: RA
authors: Notebaart
authors: Centre for Systems Biology and Bioenergetics, Radboud University Medical Centre, Nijmegen, The Netherlands; Centre for Molecular and Biomolecular Informatics, RIMLS, Radboud University Medical Center, Nijmegen, The Netherlands. Electronic address: Martijn.Huijnen@radboudumc.nl.
authors: Martijn
authors: M
authors: Huynen
authors: Department of Biochemistry, RIMLS, Radboud University Medical Center, Nijmegen, The Netherlands; Centre for Systems Biology and Bioenergetics, Radboud University Medical Centre, Nijmegen, The Netherlands. Electronic address: Peter.Willems@radboudumc.nl.
authors: Peter H G M
authors: PH
authors: Willems
authors: Department of Biochemistry, RIMLS, Radboud University Medical Center, Nijmegen, The Netherlands; Centre for Systems Biology and Bioenergetics, Radboud University Medical Centre, Nijmegen, The Netherlands. Electronic address: Werner.Koopman@radboudumc.nl.
authors: Werner J H
authors: WJ
authors: Koopman
mesh_terms: D000255:Adenosine Triphosphate / Q000378:metabolism*; D000818:Animals; D019295:Computational Biology; D042967:Electron Transport Complex I / Q000378:metabolism* / Q000502:physiology; D004734:Energy Metabolism; D007888:Leigh Disease; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008931:Mitochondria, Muscle / Q000378:metabolism*; D008962:Models, Theoretical; D018482:Muscle, Skeletal / Q000378:metabolism*; D010084:Oxidation-Reduction; D010085:Oxidative Phosphorylation; D010101:Oxygen Consumption; D011773:Pyruvates / Q000378:metabolism*
chemical_list: C534449:Ndufs4 protein, mouse; D011773:Pyruvates; D000255:Adenosine Triphosphate; D042967:Electron Transport Complex I
keywords: CI; ETC; IMS; MIM; MOM; ODE; complex I; electron transport chain; inter-membrane space; mitochondrial inner membrane; mitochondrial outer membrane; ordinary differential equation