Respiratory control and the integration of heart high-energy phosphate metabolism by mitochondrial creatine kinase.

This review has attempted to integrate three areas of cellular bioenergetics to present a novel and comprehensive view of heart high-energy phosphate metabolism. The goal has been to provide a rational view for the functions of phosphocreatine, creatine, and creatine kinase in the energy metabolism of muscle. The first point is that mitochondrial respiratory control is influenced by changes in the concentration of ADP, stimulating the adenine nucleotide translocase and oxidative phosphorylation. Secondly, as a consequence of the proximity of mitochondrial creatine kinase to the translocase, there appears to be a kinetic preference for ADP generated by the forward creatine kinase reaction. As a result, in heart, it can be viewed that the end product of oxidative phosphorylation is phosphocreatine. Finally, thermodynamic considerations suggest that phosphocreatine plays a major role to maintain or buffer the ATP content of the myocardium. Under conditions of increased ATP turnover, large-scale increases in the concentration of ADP, along with major decreases in ATP, are minimized by the creatine kinase equilibrium. The system responds to such a demand with substantial changes in phosphocreatine and creatine, which can kinetically increase the rate of mitochondrial creatine kinase and thus oxidative phosphorylation. Theoretical enzymologists have long argued whether enzymes are under kinetic or thermodynamic control. Heart creatine kinase may be a unique example where both types of control simultaneously operate in different microenvironments, with mitochondrial creatine kinase kinetically controlled, while the sarcoplasmic isozyme is influenced by equilibrium thermodynamics. Overall, heart creatine kinase may be a unique example of "kineto-dynamic" metabolic integration.