Quantitative analysis of the 'phosphocreatine shuttle': I. A probability approach to the description of phosphocreatine production in the coupled creatine kinase-ATP/ADP translocase-oxidative phosphorylation reactions in heart mitochondria

Abstract

For the first time, a probability approach was used to describe heart mitochondrial respiration in the medium with ATP, Cr and PCr but without ADP. Respiring mitochondria were considered as a three-component system, including (1) oxidative phosphorylation reactions which provide stable ATP concentration in the mitochondrial matrix; (2) adenine nucleotide translocase, which provides exchange transfer of matrix ATP for outside creatine kinase-supplied ADP when both substrates are simultaneously bound to translocase and (3) creatine kinase, starting these reactions when activated by the substrates from medium. The specific feature of this system is a close proximity of creatine kinase and translocase molecules. This results in high probability of direct activation of translocase by creatine kinase-derived ADP without its leak into the medium. In turn, the activated translocase with the same high probability directly provides creatine kinase with matrix-derived ATP. The catalytic complexes of creatine kinase with ATP from matrix together with those formed from substrates from medium provide high activation of creatine kinase coupled to translocase activation. The considered probabilities were arranged into a mathematical model. The model satisfactorily simulates the experimental data by Jacobus, W.E. and Saks, V.A. ((1982) Arch. Biochem. Biophys. 219, 167-178), who investigated this system in all regimens of functioning. The results suggest the observed kinetic and thermodynamic irregularities in the behavior of structurally-bound creatine kinase as a direct consequence of its tight coupling to translocase.