Adenine nucleotide-creatine-phosphate module in myocardial metabolic system explains fast phase of dynamic regulation of oxidative phosphorylation

Data Integration, Analysis and Logistics (DIAL) Project, Centre for Medical Systems Biology, Leiden, Rotterdam, and Amsterdam; and VU University Medical Centre, Amsterdam, The Netherlands Submitted 27 June 2006 ; accepted in final form 13 June 2007 Computational models of a large metabolic system can be assembled from modules that represent a biological function emerging from interaction of a small subset of molecules. A "skeleton model" is tested here for a module that regulates the first phase of dynamic adaptation of oxidative phosphorylation (OxPhos) to demand in heart muscle cells. The model contains only diffusion, mitochondrial outer membrane (MOM) permeation, and two isoforms of creatine kinase (CK), in cytosol and mitochondrial intermembrane space (IMS), respectively. The communication with two neighboring modules occurs via stimulation of mitochondrial ATP production by ADP and P i from the IMS and via time-varying cytosolic ATP hydrolysis during contraction. Assuming normal cytosolic diffusion and high MOM permeability for ADP, the response time of OxPhos ( t mito ; generalized time constant) to steps in cardiac pacing rate is predicted to be 2.4 s. In contrast, with low MOM permeability, t mito is predicted to be 15 s. An optimized MOM permeability of 21 µm/s gives t mito = 3.7 s, in agreement with experiments on rabbit heart with blocked glycolytic ATP synthesis. The model correctly predicts a lower t mito if CK activity is reduced by 98%. Among others, the following predictions result from the model analysis: 1 ) CK activity buffers large ADP oscillations; 2 ) ATP production is pulsatile in beating heart, although it adapts slowly to demand with "time constant" 14 heartbeats; 3 ) if the muscle isoform of CK is overexpressed, OxPhos reacts slower to changing workload; and 4 ) if mitochondrial CK is overexpressed, OxPhos reacts faster. systems biology; computational model; creatine kinase; phosphocreatine shuttle; regulatory module; mitochondrial membrane permeability; oxygen consumption Address for reprint requests and other correspondence: J. H. G. M. van Beek, Dept. of Molecular Cell Physiology, FALW, Vrije Universiteit, De Boelelaan 1085, 1081 HV Amsterdam (e-mail: hans.van.beek{at}falw.vu.nl )