Oxidative phosphorylation: unique regulatory mechanism and role in metabolic homeostasis.

Oxidative phosphorylation is the primary source of metabolic energy, in the form of ATP, in higher plants and animals, but its regulation in vivo is not well understood. A model has been developed for oxidative phosphorylation in vivo that predicts behavior patterns that are both distinctive and consistent with experimental measurements of metabolism in intact cells and tissues. A major regulatory parameter is the energy state ([ATP]/[ADP][P], where brackets denote concentration). Under physiological conditions, the [ATP] and [P] are ~100 times that of [ADP], and most of the change in energy state is through change in [ADP]. The rate of oxidative phosphorylation (-axis) increases slowly with increasing [ADP] until a threshold is reached and then increases very rapidly and linearly with further increase in [ADP]. The dependence on [ADP] can be characterized by a threshold [ADP] (T) and control strength (CS), the normalized slope above threshold (Δ/(Δ/T). For normoxic cells without creatine kinase, T is ~30 µM and CS is ~10 s Myocytes and cells with larger ranges of rates of ATP utilization, however, have the same [ADP]- and [AMP]-dependent mechanisms regulating metabolism and gene expression. To compensate, these cells have creatine kinase, and hydrolysis/synthesis of creatine phosphate increases the change in [P] and thereby CS. Cells with creatine kinase have [ADP] and [AMP], which are similar to cells without creatine kinase, despite the large differences in metabolic rate. P measurements in human muscles during work-to-rest and rest-to-work transitions are consistent with predictions of the model. A model developed for oxidative phosphorylation in vivo is shown to predict behavior patterns that are both novel and consistent with experimental measurements of metabolism in working muscle and other cells. The dependence of the rate on ADP concentration shows a pronounced threshold with a steep, nearly linear increase above the threshold. The threshold determines the homeostatic set point, and the slope above threshold determines how much metabolism changes in response to varied energy demand.