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Hysteresis and bistability in the succinate-CoQ reductase activity and reactive oxygen species production in the mitochondrial respiratory complex II.

ABSTRACT: The mitochondrial respiratory Complex II (CII) is one of key enzymes of cell energy metabolism, linking the tricarboxylic acid (TCA) cycle and the electron transport chain (ETC). CII reversibly oxidizes succinate to fumarate in the TCA cycle and transfers the electrons, produced by this reaction to the membrane quinone pool, providing ubiquinol QH₂ to ETC. CII is also known as a generator of reactive oxygen species (ROS). It was shown experimentally that succinate can serve as not only a substrate in the forward succinate-quinone oxidoreductase (SQR) direction, but also an enzyme activator. Molecular and kinetic mechanisms of this property of CII are still unclear. In order to account for activation of CII by succinate in the forward SQR direction, we developed and analyzed a computational mechanistic model of electron transfer and ROS formation in CII. It was found that re-binding of succinate to the unoccupied dicarboxylate binding site when FAD is reduced with subsequent oxidation of FADH₂ creates a positive feedback loop in the succinate oxidation. The model predicts that this positive feedback can result in hysteresis and bistable switches in SQR activity and ROS production in CII. This requires that the rate constant of re-binding of succinate has to be higher than the rate constant of the initial succinate binding to the active center when FAD is oxidized. Hysteresis and bistability in the SQR activity and ROS production in CII can play an important physiological role. In the presence of hysteresis with two stable branches with high and low SQR activity, high SQR activity is maintained even with a very strong drop in the succinate concentration, which may be necessary in the process of cell functioning in stressful situations. For the same reason, a high stationary rate of ROS production in CII can be maintained at low succinate concentrations.

SUBMITTER: Markevich NI

PROVIDER: S-EPMC7767736 | biostudies-literature | 2020 Oct

REPOSITORIES: biostudies-literature

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Hysteresis and bistability in the succinate-CoQ reductase activity and reactive oxygen species production in the mitochondrial respiratory complex II.

Markevich Nikolay I NI Galimova Miliausha H MH Markevich Lubov N LN

Redox biology 20200705

The mitochondrial respiratory Complex II (CII) is one of key enzymes of cell energy metabolism, linking the tricarboxylic acid (TCA) cycle and the electron transport chain (ETC). CII reversibly oxidizes succinate to fumarate in the TCA cycle and transfers the electrons, produced by this reaction to the membrane quinone pool, providing ubiquinol QH<sub>2</sub> to ETC. CII is also known as a generator of reactive oxygen species (ROS). It was shown experimentally that succinate can serve as not onl ...[more]

PMID: 32747163

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Project description:Background The metabolite succinate accumulates during cardiac ischemia. Within 5 minutes of reperfusion, succinate returns to baseline levels via both its release from cells and oxidation by mitochondrial complex II. The latter drives reactive oxygen species (ROS) generation and subsequent opening of the mitochondrial permeability transition (PT) pore, leading to cell death. Targeting succinate dynamics (accumulation/oxidation/release) may be therapeutically beneficial in cardiac ischemia-reperfusion (IR) injury. It has been proposed that blocking MCT1 (monocarboxylate transporter 1) may be beneficial in IR injury, by preventing succinate release and subsequent engagement of downstream inflammatory signaling pathways. In contrast, herein we hypothesized that blocking MCT1 would retain succinate in cells, exacerbating ROS generation and IR injury. Methods and Results Using the mitochondrial ROS probe mitoSOX and a custom-built murine heart perfusion rig built into a spectrofluorometer, we measured ROS generation in situ during the first moments of reperfusion. We found that acute MCT1 inhibition enhanced mitochondrial ROS generation at reperfusion and worsened IR injury (recovery of function and infarct size). Both of these effects were abrogated by tandem inhibition of mitochondrial complex II, suggesting that succinate retention worsens IR because it drives more mitochondrial ROS generation. Furthermore, using the PT pore inhibitor cyclosporin A, along with monitoring of PT pore opening via the mitochondrial membrane potential indicator tetramethylrhodamine ethyl ester, we herein provide evidence that ROS generation during early reperfusion is upstream of the PT pore, not downstream as proposed by others. In addition, pore opening was exacerbated by MCT1 inhibition. Conclusions Together, these findings highlight the importance of succinate dynamics and mitochondrial ROS generation as key determinants of PT pore opening and IR injury outcomes.

Dataset Information

Hysteresis and bistability in the succinate-CoQ reductase activity and reactive oxygen species production in the mitochondrial respiratory complex II.

Publications

Hysteresis and bistability in the succinate-CoQ reductase activity and reactive oxygen species production in the mitochondrial respiratory complex II.

Similar Datasets

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