Computer-aided studies on the regulation of oxidative phosphorylation during work transitions

In the present polemic paper the application of computer models of oxidative phosphorylation (OXPHOS) in heart, skeletal muscle and liver to the studies on the regulation of the bioenergetic system in intact cells during work transitions is discussed. Two groups of such models are compared: group I models that involve only a direct activation of ATP usage by Ca²⁺, and group II models that assume a direct activation by some (probably) Ca²⁺-related mechanism of essentially all steps of the system. It is argued that group II models reproduce much better a broad range of variable values and system properties encountered in experimental studies. The consequences of the theoretical and experimental development of Metabolic Control Analysis, within the framework of which it has been shown that the control over the flux through the oxidative phosphorylation system is shared by essentially all components of this system, are analyzed. In particular, it is argued that in order to increase the flux very significantly, and at the same time to maintain relatively constant concentrations of such intermediate metabolites as ADP, ATP, P(i), PCr and NADH, it is necessary to activate directly many, if not all components of the system (the 'multi-step parallel activation' mechanism). Generally, it is suggested that this is not a particular form or complexity of computer models, but rather their agreement with a broad range of experimental data concerning 'macroscopic' system properties that really matters. The specificity of the regulation of the energetic system of pancreatic β-cells is discussed.