ABSTRACT

Control analysis is a useful way to quantify the control of a metabolic system, and the top-down approach to metabolic control analysis is a powerful and easy-to-apply method. Top-down control analysis of oxidative phosphorylation in isolated rat liver mitochondria shows that respiration rate is controlled by proton leak across the mitochondrial inner membrane at low rates of ATP synthesis and that control at high rates of ATP synthesis is shared between the reactions of the electron transport chain and those involved in ATP synthesis and turnover. Control over the rate of ATP synthesis is differently distributed, so that the coupling efficiency varies as the respiration rate and the ATP demand vary. The control coefficients can be measured in hepatocytes, with similar results. A related approach, top-down elasticity analysis, can be used to establish the site of action of effectors such as hormones. Such analysis shows that glucagon treatment of rats stimulates the respiration rate of subsequently isolated mitochondria by changing the kinetics of the respiratory chain, whereas thyroid hormones increase respiration rate by changing the kinetics of both the proton leak and the ATP turnover reactions.