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SPECIAL SECTION ON SYSTEMS BIOLOGY OF THE MITOCHONDRION

Oxidative ATP synthesis in skeletal muscle is controlled by substrate feedback

¹Biotechnology and Bioengineering Center and Department of Physiology, Medical College of Wisconsin, Milwaukee, Wisconsin; and ²Biomedical NMR Laboratory, Department of Biomedical Engineering, Eindhoven University of Technology, Eindhoven, The Netherlands

Submitted 3 May 2006 ; accepted in final form 7 July 2006

Data from ³¹P-nuclear magnetic resonance spectroscopy of human forearm flexor muscle were analyzed based on a previously developed model of mitochondrial oxidative phosphorylation (PLoS Comp Bio 1: e36, 2005) to test the hypothesis that substrate level (concentrations of ADP and inorganic phosphate) represents the primary signal governing the rate of mitochondrial ATP synthesis and maintaining the cellular ATP hydrolysis potential in skeletal muscle. Model-based predictions of cytoplasmic concentrations of phosphate metabolites (ATP, ADP, and P_i) matched data obtained from 20 healthy volunteers and indicated that as work rate is varied from rest to submaximal exercise commensurate increases in the rate of mitochondrial ATP synthesis are effected by changes in concentrations of available ADP and P_i. Additional data from patients with a defect of complex I of the respiratory chain and a patient with a deficiency in the mitochondrial adenine nucleotide translocase were also predicted the by the model by making the appropriate adjustments to the activities of the affected proteins associates with the defects, providing both further validation of the biophysical model of the control of oxidative phosphorylation and insight into the impact of these diseases on the ability of the cell to maintain its energetic state.

computational model; mitochondria; cellular energetics; oxidative phosphorylation; ³¹P-NMR spectroscopy

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