Zagubnaya Olga A, Selivanov Vitaly A, Pekker Mark, Jonkhout Carel J H, Nartsissov Yaroslav R, Cascante Marta
Department of Mathematical Modeling and Statistical Analysis, Institute of Cytochemistry and Molecular Pharmacology, Moscow 115404, Russia.
Biomedical Research Group, BiDipharma, Bültbek 5, 22962 Siek, Germany.
Cells. 2025 Jul 1;14(13):1006. doi: 10.3390/cells14131006.
We have previously shown that the mitochondrial respiratory chain (RC) can switch between the following two states: (i) an "ATP-producing" state characterized by the low production of reactive oxygen species (ROS), the vigorous translocation of hydrogen ions (H), and the storage of energy from the H gradient in the form of ATP, and (ii) an "ROS-producing" state, where the translocation of H is slow but the production of ROS is high. Here, we suggest that the RC transition from an ATP-producing to an ROS-producing state initiates a mitochondrial permeability transition (MPT) by generating a burst of ROS. Numerous MPT activators induce the transition of the RC to an ROS-producing state, and the ROS generated in this state activate the MPT. The MPT, in turn, induces changes in conditions that are necessary for the RC to return to an ATP-producing state, decreasing the ROS production rate and restoring the normal permeability of the inner membrane. In this way, the transient MPT prevents cell damage from oxidative stress that would occur if the RC remained in an ROS-producing state. It is shown that an overload of glutamate, which enters through excitatory amino acid transporters (EAATs), induces the RC to switch to an ROS-producing state. Subsequent MPT activation causes a transition back to an ATP-producing state. The model was used to predict the spatial-temporal dynamics of glutamate concentrations and HO production rates in a three-dimensional digital phantom of nervous tissue.
我们之前已经表明，线粒体呼吸链（RC）可以在以下两种状态之间切换：（i）一种“产生ATP”的状态，其特征是活性氧（ROS）产生量低、氢离子（H）大量转运以及以ATP形式储存来自H梯度的能量；（ii）一种“产生ROS”的状态，其中H的转运缓慢但ROS的产生量高。在此，我们认为呼吸链从产生ATP的状态转变为产生ROS的状态会通过产生一阵ROS引发线粒体通透性转换（MPT）。许多MPT激活剂会诱导呼吸链转变为产生ROS的状态，并且在这种状态下产生的ROS会激活MPT。反过来，MPT会诱导呼吸链恢复到产生ATP状态所需条件的变化，降低ROS产生速率并恢复内膜的正常通透性。通过这种方式，短暂的MPT可防止细胞因呼吸链若保持在产生ROS状态时会发生的氧化应激而受损。研究表明，通过兴奋性氨基酸转运体（EAATs）进入的谷氨酸过载会诱导呼吸链切换到产生ROS的状态。随后的MPT激活会导致转变回产生ATP的状态。该模型被用于预测神经组织三维数字模型中谷氨酸浓度和HO产生速率的时空动态。
