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

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Alam, Mohammad T., Manjeri, Ganesh R, Rodenburg, Richard J, Smeitink, Jan A M, Notebaart, Richard A, Huynen, Martijn, Willems, Peter H G M and Koopman, Werner J H (2015) Skeletal muscle mitochondria of NDUFS4-/- mice display normal maximal pyruvate oxidation and ATP production. Biochimica et biophysica acta, 1847 (6-7). pp. 526-33. doi:10.1016/j.bbabio.2015.02.006 ISSN 0006-3002.

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Official URL: http://dx.doi.org/10.1016/j.bbabio.2015.02.006

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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.

Item Type: Journal Article
Divisions: Faculty of Science, Engineering and Medicine > Medicine > Warwick Medical School > Biomedical Sciences > Microbiology & Infection
Faculty of Science, Engineering and Medicine > Medicine > Warwick Medical School
Journal or Publication Title: Biochimica et biophysica acta
Publisher: Elsevier BV
ISSN: 0006-3002
Official Date: June 2015
Dates:
DateEvent
June 2015Published
14 February 2015Available
13 August 2014Submitted
7 February 2015Accepted
Volume: 1847
Number: 6-7
Page Range: pp. 526-33
DOI: 10.1016/j.bbabio.2015.02.006
Status: Peer Reviewed
Publication Status: Published
Access rights to Published version: Restricted or Subscription Access

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