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

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Skeletal muscle mitochondria of NDUFS4-/- mice display normal maximal pyruvate oxidation and ATP production. / Alam, Mohammad T; Manjeri, Ganesh R; Smeitink, Jan A M; Notebaart, Richard A; Huynen, Martijn.

In: Biochimica et Biophysica Acta, Vol. 1847, No. 6-7, 18.02.2015, p. 526-33.

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Alam, Mohammad T ; Manjeri, Ganesh R ; Smeitink, Jan A M ; Notebaart, Richard A ; Huynen, Martijn. / Skeletal muscle mitochondria of NDUFS4-/- mice display normal maximal pyruvate oxidation and ATP production. In: Biochimica et Biophysica Acta. 2015 ; Vol. 1847, No. 6-7. pp. 526-33.

Bibtex

@article{ceba08032d244fbaa4315d63e0b56c72,
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.",
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",
author = "Alam, {Mohammad T} and Manjeri, {Ganesh R} and Smeitink, {Jan A M} and Notebaart, {Richard A} and Martijn Huynen",
note = "Copyright {\textcopyright} 2015 Elsevier B.V. All rights reserved.",
year = "2015",
month = feb
day = "18",
doi = "10.1016/j.bbabio.2015.02.006",
language = "English",
volume = "1847",
pages = "526--33",
journal = "Biochimica et Biophysica Acta",
issn = "1874-9399",
publisher = "Elsevier",
number = "6-7",

}

RIS

TY - JOUR

T1 - Skeletal muscle mitochondria of NDUFS4-/- mice display normal maximal pyruvate oxidation and ATP production

AU - Alam, Mohammad T

AU - Manjeri, Ganesh R

AU - Smeitink, Jan A M

AU - Notebaart, Richard A

AU - Huynen, Martijn

N1 - Copyright © 2015 Elsevier B.V. All rights reserved.

PY - 2015/2/18

Y1 - 2015/2/18

N2 - 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.

AB - 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.

KW - Adenosine Triphosphate

KW - Animals

KW - Computational Biology

KW - Electron Transport Complex I

KW - Energy Metabolism

KW - Leigh Disease

KW - Mice

KW - Mice, Inbred C57BL

KW - Mice, Knockout

KW - Mitochondria, Muscle

KW - Models, Theoretical

KW - Muscle, Skeletal

KW - Oxidation-Reduction

KW - Oxidative Phosphorylation

KW - Oxygen Consumption

KW - Pyruvates

U2 - 10.1016/j.bbabio.2015.02.006

DO - 10.1016/j.bbabio.2015.02.006

M3 - Article

C2 - 25687896

VL - 1847

SP - 526

EP - 533

JO - Biochimica et Biophysica Acta

JF - Biochimica et Biophysica Acta

SN - 1874-9399

IS - 6-7

ER -