Role of the creatine/phosphocreatine system in the regulation of mitochondrial respiration

The mechanism of metabolic regulation of mitochondrial respiration in cardi ac muscle cells was studied experimentally in the permeabilized heart fibre s of mice and by computer modelling in silico. The experiments showed that the rate of mitochondrial respiration could be controlled by local producti on of ADP by mitochondrial creatine kinase in the intermembrane space of mi tochondria. The spatially inhomogenous reaction-diffusion model of compartm entalized energy transfer was used to analyse which metabolite level in cyt oplasm may be important for regulation of respiration. At low and moderate workloads, up to VO2 equal to 70 mu mol min(-1) g(-1) dry weight, the only factor to which respiration responded was inorganic phosphate. At the value s of VO2 higher than 70 mu mol min(-1) g(-1) dry weight, the respiration ra te responded mostly to changes in creatine, phosphocreatine and then time-a veraged (over the contractile cycle) ADP concentrations in the cytoplasm. T hese results are taken to show that under conditions of moderate workloads, creatine kinase activity at given physiological creatine and phosphocreati ne concentrations (apparent maximal activity achievable under these conditi ons) is in excess to oxidative phosphorylation rate, which is controlled by P-i concentration changes starting from very low values of the latter. At higher workloads mi-CK should be upregulated by increasing creatine and dec reasing phosphocreatine concentrations, and only at very high workloads the ADP diffusion flux should be increased to upregulate oxidative phosphoryla tion. Thus, on the basis of the study in silico of compartmentalized energy transfer by phophocreatine/creatine system, the authors conclude that ther e exist multiple parallel regulatory factors controlling the rate of oxygen consumption in dependence of the workload. If creatine kinase is inhibited (and there is no myokinase activity), respiration requires high diffusive flux of ADP back into mitochondria, which is the sole regulator of respirat ion. This needs, however, increased ADP concentrations in the cytoplasm, wh ich in turn result in inhibition of contraction.