Akopova O. The role of the mitochondrial pore in the regulation of transmembrane exchange of Ca2+, energy-dependent and free radical processes in mitochondria

The thesis is devoted to the establishment of the properties and the regulation of activity of mitochondrial permeability transition pore (MPTP) as Ca2+ transport system and the disclosure of its role in the modulation of processes, dependent on mitochondrial energy state - ATP synthesis and reactive oxygen species (ROS) production. It was established that the role of MPTP as Ca2+ efflux system, which is regulated by Ca2+ and membrane potential, provides wide spectrum of its regulatory functions: the transmembrane exchange of Ca2+, the regulation of Ca2+ accumulation and matrix pH, the contribution to Ca2+ cycling and the regulation of potential-dependent processes. In low activity states bioenergetic effects of MPTP opening are dependent on MPTP properties as Ca2+ transport system and its contribution to Ca2+ cycle, the rate of Ca2+ stimulated respiration and the modulation of membrane potential. MPTP opening in low activity states results in the reversible functional alterations in mitochondria: mild uncoupling of the respiratory chain which does not affect the rate of ATP synthesis, and controlled rate of ROS production. Some principal aspects of the regulation of MPTP activity under the activation of K+atp-channel and NO system were established. It was shown that synchronized activation of K+- and Са2+ cycles due to MPTP and K+atp-channel activity causes synergistic effect in the suppression of ROS production, which was proposed as the principal mechanism of MPTP keeping in low activity states under the action of K+atp-channel opener. It was shown that МРТР blockage by NO results in the rise of Са2+ uptake and the activation of free radical processes, whereas the regulatory role of MPTP functioning in low activity states is aimed at the maintenance of low basal level of matrix Са2+ and the lowering of free radical production in mitochondria.