Regulation of mitochondrial respiration in heart cells analyzed by reaction-diffusion model of energy transfer

Abstract

The purpose of this study is to investigate theoretically which intracellular factors may be important for regulation of mitochondrial respiration in working heart cells in vivo. We have developed a model that describes quantitatively the published experimental data on dependence of the rate of oxygen consumption and metabolic state of working isolated perfused rat heart on workload over its physiological range (Williamson JR, Ford G, Illingworth J, Safer B. Circ Res 38, Suppl I, I39-I51, 1976). Analysis of this model shows that for phosphocreatine, creatine, and ATP the equilibrium assumption is an acceptable approximation with respect to their diffusion in the intracellular bulk water phase. However, the ADP concentration changes in the contraction cycle in a nonequilibrium workload-dependent manner, showing the existence of the intracellular concentration gradients. The model shows that workload-dependent alteration of ADP concentration in the compartmentalized creatine kinase system may be taken, together with the changes in P(i) concentration, to be among the major components of the metabolic feedback signal for regulation of respiration in muscle cells.

A Biophysical Model of the Mitochondrial Respiratory System and Oxidative Phosphorylation

“…For example, the widely used model of Korzeniewski and Zoladz [4][5][6] invokes an empirical linear relationship between the difference in pH across the mitochondrial inner membrane (matrix pH minus cytosol pH) and the magnitude of inner membrane potential. While the Korzeniewski model has been validated and verified based on a number of studies and is widely applied [7][8][9], the central empirical relationship between electrostatic potential and pH difference is not expected to apply under all conditions. For example, in the extensive study of isolated cardiac mitochondria published by Bose et al [10], this relationship is not obeyed.…”

Regulation of oxidative phosphorylation through parallel activation

“…Jeneson and co-workers [5] modified this mechanism and postulated that the mechanistic VO 2 -[ADP] dependence is actually much steeper, at least second order (this modified output-activation mechanism can be called the mechanisticultrasensitivity mechanism, Mechanism D). Finally, Saks and co-workers [6][7][8] supplemented the original output-activation mechanism with the assumption that in intact muscle there exist significant ADP diffusion gradients and therefore creatine kinase (CK) is significantly displaced from thermodynamic equilibrium, what has a significant impact on the kinetic properties of oxidative phosphorylation (let us call this mechanism the CK-disequilibrium mechanism, Mechanism E).…”

Skeletal muscle energetics with PNMR: personal views and historic perspectives

“…More recent measures of the ATP/ADP ratio, and particularly of the cytosolic ATP free energy, give higher estimates, in the range from À60 to À63 kJ/mol (41). These matters will be illuminated further only by careful measurements of the distances involved and by simulations of reactiondiffusion equations, as have been started (66,67).…”