The effect of Са(2+)-induced opening of cyclosporine-sensitive pore on the oxygen consumption and functional state of rat liver mitochondria

摘要

The effect of Casup2+/sup-induced opening of cyclosporine-sensitive pore (mitochondrial permeability transition pore, MPTP) on the oxygen consumption and mitochondrial functional state was studied in the rat liver mitochondria. It was shown that, with the use of glutamate as oxidation substrate, in the absence of depolarization MPTP opening results in the increase of steady state respiration rate because of the activation of cyclosporine-sensitive Casup2+/sup/Hsup+/sup-exchange and Casup2+/sup cycling, which was supported by the simultaneous work of MPTP and Casup2+/sup-uniporter. With the aid of selective blockers, cyclosporine A and ruthenium red, it was shown that MPTP and Casup2+/sup-uniporter contribute equally to the Casup2+/sup-cycling and mitochondrial respiration. It was shown that bioenergetic effects of MPTP opening under steady state conditions (increase in the oxygen consumption rate under substrate oxidation without ADP, decrease in respiratory control ratio as well as the effectiveness of ATP synthesis, P/O) are close to the functional alterations, which result from the increase of endogenous proton conductance of mitochondrial membrane. Uncoupling effect of MPTP opening, by itself, had no effect on phosphorylation rate, which remains relatively stable because the fall of P/O is compensated by the activation of respiratory chain and the increase in the rate of state 3 respiration. It was concluded that under physiologically normal conditions MPTP might function as the endogenous mechanism of mild uncoupling of respiratory chain.