Integration of demand and supply sides in the ATP energy economics of cells

Abstract

The central aspects of the energy economics of living cells revolve around the synthesis and utilization of molecules of adenosine triphosphate (ATP). Current descriptions of cell metabolism and its regulation in most textbooks of biochemistry assume that enzymes and transporters behave in the same way in isolation and in a cell. Calculations of the mechanistic or maximal P/O ratios in oxidative phosphorylation by mammalian cells generally consider only the supply side of the problem without linking to ATP-demand processes. The purpose of this article is to calculate the mechanistic P/O ratio by integration of the supply and demand sides of ATP reactions. The mechanistic stoichiometry calculated from an integrated approach is compared with that obtained from the standard model that considers only ATP supply. After accounting for leaks, slips, and other losses, the actual or operative P/O calculated by the integrated method is found to be in good agreement with the experimental values of the P/O ratio determined in mitochondria for both succinate and NADH-linked respiratory substrates. The thermodynamic consequences of these results and the biological implications are discussed. An integrated model of oxidative phosphorylation that goes beyond the chemiosmotic theory is presented, and a solution to the longstanding fundamental problem of respiratory control is found.

Keywords: Adenosine triphosphate (ATP); Coupling of ATP synthesis to oxygen consumption/respiration; Dicarboxylic acids; Energy demand management/economics in biology; Homeostasis; Metabolic engineering; Metabolic regulation and control; Nath's torsional mechanism of energy transduction and ATP synthesis; Nath's two-ion theory of biological energy coupling; Oxidative phosphorylation; P/O ratio; Succinate.