Akopova O V, Kolchynskayia L Y, Nosar' V Y, Smyrnov A N, Malisheva M K, Man'kovskaia Y N, Sahach V F
Bogomoletz Institute of Physiology, National Academy of Sciences of Ukraine, Kyiv.
Ukr Biokhim Zh (1999). 2011 Nov-Dec;83(6):46-55.
The influence of mitochondrial permeability transition pore (MPTP) opening on reactive oxygen species (ROS) production in the rat brain mitochondria was studied. It was shown that ROS production is regulated differently by the rate of oxygen consumption and membrane potential, dependent on steady-state or non-equilibrium conditions. Under steady-state conditions, at constant rate of Ca2+-cycling and oxygen consumption, ROS production is potential-dependent and decreases with the inhibition of respiration and mitochondrial depolarization. The constant rate of ROS release is in accord with proportional dependence of the rate of ROS formation on that of oxygen consumption. On the contrary, transition to non-equilibrium state, due to the release of cytochrome c from mitochondria and progressive respiration inhibition, results in the loss of proportionality in the rate of ROS production on the rate of respiration and an exponential rise of ROS production with time, independent of membrane potential. Independent of steady-state or non-equilibrium conditions, the rate of ROS formation is controlled by the rate of potential-dependent uptake of Ca2+ which is the rate-limiting step in ROS production. It was shown that MPTP opening differently regulates ROS production, dependent on Ca2+ concentration. At low calcium MPTP opening results in the decrease in ROS production because of partial mitochondrial depolarization, in spite of sustained increase in oxygen consumption rate by a cyclosporine A-sensitive component due to simultaneous work of Ca2+-uniporter and MPTP as Ca2+-influx and efflux pathways. The effect of MPTP opening at low Ca2+ concentrations is similar to that of Ca2+-ionophore, A-23187. At high calcium MPTP opening results in the increase of ROS release due to the rapid transition to non-equilibrium state because of cytochrome c loss and progressive gating of electron flow in respiratory chain. Thus, under physiological conditions MPTP opening at low intracellular calcium could attenuate oxidative damage and the impairment of neuronal functions by diminishing ROS formation in mitochondria.
研究了线粒体通透性转换孔（MPTP）开放对大鼠脑线粒体活性氧（ROS）生成的影响。结果表明，在稳态或非平衡条件下，ROS生成受氧消耗速率和膜电位的调节方式不同。在稳态条件下，当Ca2+循环和氧消耗速率恒定时，ROS生成与电位相关，随着呼吸抑制和线粒体去极化而降低。ROS释放的恒定速率与ROS形成速率对氧消耗速率的比例依赖性一致。相反，由于线粒体细胞色素c的释放和呼吸的逐渐抑制而转变为非平衡状态时，ROS生成速率与呼吸速率之间的比例关系丧失，且ROS生成随时间呈指数上升，与膜电位无关。无论在稳态还是非平衡条件下，ROS形成速率均受电位依赖性Ca2+摄取速率的控制，而这是ROS生成中的限速步骤。结果表明，MPTP开放对ROS生成的调节因Ca2+浓度而异。在低钙条件下，MPTP开放导致ROS生成减少，这是由于线粒体部分去极化，尽管由于Ca2+单向转运体和MPTP作为Ca2+流入和流出途径同时作用，环孢素A敏感成分使氧消耗速率持续增加。低Ca2+浓度下MPTP开放的作用与Ca2+离子载体A-23187相似。在高钙条件下，MPTP开放导致ROS释放增加，这是由于细胞色素c丢失和呼吸链中电子流的逐渐门控，从而迅速转变为非平衡状态。因此，在生理条件下，细胞内低钙时MPTP开放可通过减少线粒体中ROS的形成来减轻氧化损伤和神经元功能损害。
