Prediction of Muscle Energy States at Low Metabolic Rates Requires Feedback Control of Mitochondrial Respiratory Chain Activity by Inorganic Phosphate

• Published in: PloS one Vol. 7; no. 3; p. e34118
• Main Authors: Schmitz, Joep P. J., Jeneson, Jeroen A. L., van Oorschot, Joep W. M., Prompers, Jeanine J., Nicolay, Klaas, Hilbers, Peter A. J., van Riel, Natal A. W.
• Format: Journal Article
• Language: English
• Published: United States Public Library of Science 28.03.2012; Public Library of Science (PLoS)
• Subjects: Activation; Adenosine diphosphate; Adenosine Diphosphate - metabolism; Analysis; Athletes; ATP; Bioinformatics; Biology; Biomedical engineering; Chain dynamics; Chains; Computer simulation; Consortia; Control; Control systems; Cytochrome b; Data recovery; Diabetes; Dynamic range; Electron transport; Electron Transport Complex III - metabolism; Energy; Energy Metabolism; Engineering; Feedback; Feedback control; Fluctuations; Fluxes; Free energy; Homeostasis; Humans; Hypotheses; Kinases; Magnetic resonance; Magnetic Resonance Spectroscopy; Mathematical models; Medicine; Membrane Potential, Mitochondrial; Metabolism; Metabolites; Mitochondria; Mitochondria, Muscle - metabolism; Models, Theoretical; Monte Carlo methods; Monte Carlo simulation; Muscle, Skeletal - metabolism; Muscles; Musculoskeletal system; NMR; Nuclear magnetic resonance; Nuclear magnetic resonance spectroscopy; Oxidative phosphorylation; Parameterization; Phosphates; Phosphates - metabolism; Phosphocreatine; Phosphorylation; Physiology; Respiration; Simulation; Skeletal muscle; Spectroscopy; Spectrum analysis; Synthesis; Thermodynamics; Type 2 diabetes; Netherlands
• ISSN: 1932-6203; 1932-6203
• DOI: 10.1371/journal.pone.0034118

The regulation of the 100-fold dynamic range of mitochondrial ATP synthesis flux in skeletal muscle was investigated. Hypotheses of key control mechanisms were included in a biophysical model of oxidative phosphorylation and tested against metabolite dynamics recorded by (31)P nuclear magnetic resonance spectroscopy ((31)P MRS). Simulations of the initial model featuring only ADP and Pi feedback control of flux failed in reproducing the experimentally sampled relation between myoplasmic free energy of ATP hydrolysis (ΔG(p) = ΔG(p)(o')+RT ln ([ADP][Pi]/[ATP]) and the rate of mitochondrial ATP synthesis at low fluxes (<0.2 mM/s). Model analyses including Monte Carlo simulation approaches and metabolic control analysis (MCA) showed that this problem could not be amended by model re-parameterization, but instead required reformulation of ADP and Pi feedback control or introduction of additional control mechanisms (feed forward activation), specifically at respiratory Complex III. Both hypotheses were implemented and tested against time course data of phosphocreatine (PCr), Pi and ATP dynamics during post-exercise recovery and validation data obtained by (31)P MRS of sedentary subjects and track athletes. The results rejected the hypothesis of regulation by feed forward activation. Instead, it was concluded that feedback control of respiratory chain complexes by inorganic phosphate is essential to explain the regulation of mitochondrial ATP synthesis flux in skeletal muscle throughout its full dynamic range.