A simplified model for mitochondrial ATP production

Abstract

Most of the adenosine triphosphate (ATP) synthesized during glucose metabolism is produced in the mitochondria through oxidative phosphorylation. This is a complex reaction powered by the proton gradient across the mitochondrial inner membrane, which is generated by mitochondrial respiration. A detailed model of this reaction, which includes dynamic equations for the key mitochondrial variables, was developed earlier by Magnus and Keizer. However, this model is extraordinarily complicated. We develop a simpler model that captures the behavior of the original model but is easier to use and to understand. We then use it to investigate the mitochondrial responses to glycolytic and calcium input. We use the model to explain experimental observations of the opposite effects of raising cytosolic Ca(2+)in low and high glucose, and to predict the effects of a mutation in the mitochondrial enzyme nicotinamide nucleotide transhydrogenase (Nnt) in pancreatic beta-cells.