SIMULATION OF STATE-4-]STATE-3 TRANSITION IN ISOLATED-MITOCHONDRIA

The mathematical dynamic model of oxidative phosphorylation developed previously and in the accompanying paper was modified to involve isola ted mitochondria conditions; it was also used to simulate state 4 --> state 3 transition in rat liver mitochondria incubated with succinate as respiratory substrate and glucose-hexokinase as an ADP-regenerating system. Changes in the respiration rare, protonmotive force and reduc tion level of ubiquinone and cytochrome c as well as the internal (i) and external (e) ATP/ADP ratio between state 4 and slate 3 were calcul ated and compared with the experimental data. Flux control coefficient s with respect to oxygen consumption flux for different reactions and processes of oxidative phosphorylation were simulated for different va lues of the respiration rate (state 4, state 3 and intermediate states ). Flux control coefficients for the oxidation, phosphorylation and pr oton leak subsystems with respect to the oxidation, phosphorylation an d proton leak fluxes for different values of the respiration rate were also calculated. These theoretical data were compared with the experi mental results obtained in the frame of metabolic control analysis and the 'top-down' approach to this analysis. A good agreement was obtain ed. Simulated time courses of the respiration rate, the protonmotive f orce (Delta p) and other parameters after addition of a small amount o f ADP to mitochondria in state 4 mimicked at least semiquantitatively the experimentally measured time courses of these parameters. It was c oncluded, therefore, that in the present stage, the model is able to r eflect different properties of the oxidative phosphorylation system in a broad range of conditions fairly well, allows deeper insight into t he mechanisms responsible for control and regulation of this process, and can be used for simulation of new experiments, thus inspiring expe rimental verification of the theoretical predictions.