Regulation of the tricarboxylic acid cycle and beta-oxidation by excess substrates

A simple mathematical model is proposed to explain the inhibition of beta-oxidation and of the tricarboxylic acid cycle by excess of fatty acids. This model is based on the peculiar stoichiometry of beta-oxidation reactions, which accounts for the formation of dynamical traps for free CoA and its esters in the form of 3-ketoacyl-CoA derivatives. It follows from the analysis of the model that the fatty acids can produce 100% inhibition of respiration at some critical concentrations depending on their chain lengths. This conclusion was confirmed by experiments with rat liver mitochondria. The critical concentrations determined at high respiratory rates (85% of state 3 respiration) for palmitoylcarnitine, capric acid and caproic acid were found to be 0.45 mM, 1.8-2 mM and 3 mM, respectively.