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 QH 2 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 FADH 2 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.

Synthesis and Photoactivated Toxicity of 2-Thiophenylfuranocoumarin Induce Midgut Damage and Apoptosis in Aedes aegypti Larvae

“…The mitochondria were damaged by the Iy treatment, and the enzyme activities of ETC complexes were inhibited at different degrees, which especially applied to the respiratory complex III enzymes. Some earlier studies showed that a respiratory complex II key enzyme, which connects the ETC to the TCA, can also be a site of ROS production. ,, The activities of key enzymes in the TCA cycle are also inhibited by Iy in varying degrees. Interestingly, some studies have shown that α-KGDH can also participate in the production of ROS. , Furthermore, the function of mitochondria is highly dependent on MMP as a critical parameter for the real-time state of mitochondria, which plays an important role in maintaining biosynthesis and apoptosis. − Therefore, it was speculated that the decrease in MMP might play a key role in inducing apoptosis.…”

Identifying Site-specific Superoxide and Hydrogen Peroxide Production Rates from the Mitochondrial Electron Transport System Using a Computational Strategy

“…While several mitochondrial ROS models exist 41,42,[53][54][55][56] , none can reproduce the wide variety of available mitochondrial bioenergetic data quantitatively and consistently. These models either lack the biophysical details to simulate the enzymatic reactions associated with both high and low electron flux regimes 42,56 or exclude complex II as a ROS-producing component 53 .…”

Reactive oxygen species-based nanomaterials for the treatment of myocardial ischemia reperfusion injuries

“…In RET process, electrons first enter complex II through succinate oxidation and reach CoQ, and then are directed back to complex I instead of proceeding forward to complex III [ 47 , 82 , 94 ]. Succinates from ischemic accumulation are rapidly re-oxidized by the succinate dehydrogenase of complex II, which transfers electrons from complex II to complex I, and produces O 2 ·− [ 90 , 95 ]. Complex III also triggers O 2 ·− production through the redox reactions between oxygen and ubisemiquinone [ 38 , 47 , 96 ].…”