Regulation analysis of energy metabolism.

This paper reviews top-down regulation analysis, a part of metabolic control analysis, and shows how it can be used to analyse steady states, regulation and homeostasis in complex systems such as energy metabolism in mitochondria, cells and tissues. A steady state is maintained by the variables in a system; regulation is the way the steady state is changed by external effectors. We can exploit the properties of the steady state to measure the kinetic responses (elasticities) of reactions to the concentrations of intermediates and effectors. We can reduce the complexity of the system under investigation by grouping reactions into large blocks connected by a small number of explicit intermediates-this is the top-down approach to control analysis. Simple titrations then yield all the values of elasticities and control coefficients within the system. We can use these values to quantify the relative strengths of different internal pathways that act to keep an intermediate or a rate constant in the steady state. We can also use them to quantify the relative strengths of different primary actions of an external effector and the different internal pathways that transmit its effects through the system, to describe regulation and homeostasis. This top-down regulation analysis has been used to analyse steady states of energy metabolism in mitochondria, cells and tissues, and to analyse regulation of energy metabolism by cadmium, an external effector, in mitochondria. The combination of relatively simple experiments and new theoretical structures for presenting and interpreting the results means that top-down regulation analysis provides a novel and effective way to analyse steady states, regulation and homeostasis in intricate metabolic systems.