Mathematical Modeling of ROS Production and Diode-like Behavior in the SDHA/SDHB Subcomplex of Succinate Dehydrogenases in Reverse Quinol-Fumarate Reductase Direction
Abstract
:1. Introduction
2. Results and Discussion
2.1. Eout Dependency of the Total Rate of Reverse Electron Transfer in SDH
2.2. Eout Dependency of the Rate of Succinate Production in SDH
2.3. Computational Analysis of the ROS Production Rate in the SDHA/SDHB Subcomplex during Reverse Electron Transfer
2.4. Dependence of the Rate of Succinate Production on the Fumarate Concentration in SDH
3. Methods and Models
3.1. Kinetic Model of Reverse Electron Transfer in SDHA/SDHB Subunits of SDH
- (1)
- Keq4 ∙ Keq5 ∙ Keq6 ∙Keq7 ∙ Keq8 = 1;
- (2)
- Keq6 ∙ Keq10/(Keq11 ∙ Keq12) = 1;
- (3)
- Keq8 ∙ Keq9/(Keq13 ∙ Keq14) = 1;
- (4)
- Keq7 ∙ Keq12 ∙ Keq13 ∙Keq15 ∙ Keq16 = 1.
3.2. Computational Model of Reverse Electron Transfer in SDHA/SDHB Subunits of SDH. Mathematical Model
4. Conclusions
Supplementary Materials
Author Contributions
Funding
Institutional Review Board Statement
Informed Consent Statement
Data Availability Statement
Acknowledgments
Conflicts of Interest
Abbreviations
References
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No | Reaction | Rate Equation |
---|---|---|
1 | e− + [3Fe-4S] = [3Fe-4S]− | V1 = k1 ∙ ([3Fe-4S] ∙ exp(-α ∙ F ∙ Eout/RT) − [3Fe-4S]− ∙ exp((1-α) ∙ F ∙ Eout/RT)/Keq1) |
2 | [4Fe-4S] + [3Fe-4S]− = [4Fe-4S]− + [3Fe-4S] | V2 = k2 ∙ ([4Fe-4S] ∙ [3Fe-4S]− − [4Fe-4S]− ∙ [3Fe-4S]/Keq2) |
3 | [2Fe-2S] + [4Fe-4S]− = [2Fe-2S]− + [4Fe-4S] | V3 = k3 ∙ ([2Fe-2S] ∙ [4Fe-4S]− − [2Fe-2S]− ∙ [4Fe-4S]/Keq3) |
4 | FAD + fum = FAD.fum | V4 = k4 ∙ (FAD ∙ fum − FAD.fum/Keq4) |
5 | FAD.fum + [2Fe-2S]− + H + = FADH•.fum + [2Fe-2S] | V5 = k5 ∙ (FAD.fum ∙ [2Fe-2S]− ∙ H + − FADH•.fum ∙ [2Fe-2S]/Keq5) |
6 | FADH•.fum + [2Fe-2S]− + H + = FADH2.fum + [2Fe-2S] | V6 = k6 ∙ (FADH•.fum ∙ [2Fe-2S]− ∙ H + − FADH2.fum ∙ [2Fe-2S]/Keq6) |
7 | FADH2.fum = FAD.suc | V7 = k7 ∙ (FADH2.fum − FAD.suc/Keq7) |
8 | FAD.suc = FAD + suc | V8 = k9 ∙ (FAD.suc − FAD ∙ suc/Keq8) |
9 | FAD + [2Fe-2S]− + H + = FADH• + [2Fe-2S] | V9 = k9 ∙ (FAD ∙ [2Fe-2S]− ∙ H + − FADH• ∙ [2Fe-2S]/Keq9) |
10 | FADH• + fum = FADH•.fum | V10 = k10 ∙ (FADH• ∙ fum − FADH•.fum/Keq10) |
11 | FADH• + [2Fe-2S]− + H + = FADH2 + [2Fe-2S] | V11 = k11 ∙ (FADH• ∙ [2Fe-2S]− ∙ H + − FADH2 ∙ [2Fe-2S]/Keq11) |
12 | FADH2 + fum = FADH2.fum | V12 = k12 ∙ (FADH2 ∙ fum − FADH2.fum/Keq12) |
13 | FAD.suc + [2Fe-2S]− + H + = FADH•.suc + [2Fe-2S] | V13 = k13 ∙ (FAD.suc ∙ [2Fe-2S]− ∙ H + − FADH•.suc ∙ [2Fe-2S]/Keq13) |
14 | FADH•.suc = suc + FADH• | V14 = k14 ∙ (FADH•.suc − FADH• ∙ suc/Keq14) |
15 | FADH•.suc + [2Fe-2S]− + H + = FADH2.suc + [2Fe-2S] | V15 = k15 ∙ (FADH•.suc ∙ [2Fe-2S]− ∙ H + − FADH2.suc ∙ [2Fe-2S]/Keq15) |
16 | FADH2.suc = suc + FADH2 | V16 = k16 ∙ (FADH2.suc − FADH2 ∙ suc/Keq16) |
Hydrogen peroxide (H2O2) production by SDH | ||
17 | FADH2 + O2 = FAD + H2O2 | V17 = k17 ∙ (FADH2 ∙ O2 − FAD ∙ H2O2/Keq17) |
Superoxide anion (O2∙−) production by the subcomplex SDHA/SDHB of SDH | ||
18 | FADH2 + O2 = FADH• + O2∙− + H + | V18 = k18 ∙ (FADH2 ∙ O2 − FADH• ∙ O2∙− ∙ H + /Keq18) |
19 | FADH• + O2 = FAD + O2∙− + H + | V19 = k19 ∙ (FADH• ∙ O2 − FAD ∙ O2∙− ∙ H + /Keq19) |
20 | [3Fe-4S]− + O2 = [3Fe-4S] + O2∙− | V20 = k20 ∙ ([3Fe-4S]− ∙ O2 − [3Fe-4S] ∙ O2∙−/Keq20) |
Superoxide anion dismutation in the mitochondrial matrix | ||
21 | 2 O2∙− + 2H + → O2 + H2O2 | V21 = Vmax21 ∙ O2∙−/(Km21 + O2∙−) |
Release of hydrogen peroxide (H2O2) from the mitochondrial matrix to cytosol | ||
22 | H2O2 → | V22 = k22 ∙ H2O2 |
Reaction No | Midpoint Potential Em = E, (mV) | Equilibrium Constant Keq | kforward | Other Parameters | Reference |
---|---|---|---|---|---|
1 | E([3Fe-4S]) = 60 | 11.023 | 1∙103 s−1 | α = 0.5 α is a certain coefficient that varies from 0 to 1. Eout—electrode potential. F, R and T have a usual meaning. | [17] a |
2 | E([4Fe-4S]) = −260 E([3Fe-4S]) = 60 | 2.78∙10−6 | 1∙104 µM−1·s−1 | pH = 7.4 | [17,18] a |
3 | E([2Fe-2S]) = 0 E([4Fe-4S]) = −260 | 3.29∙104 | 1∙104 µM−1·s−1 | pH = 7.4 | [18] a |
4 | 4.17∙10−3 µM−1 | 1 s−1 | [15] b | ||
5 | E(FAD/FADH•) = −127 E([2Fe-2S]) = 0 | 0.03 e µM−1 | 1∙103 µM−2·s−1 | pH = 7 pH = 7.4 | [18,19] a |
6 | E(FADH•/FADH2) = −31 E([2Fe-2S]) = 0 | 0.289 e µM−1 | 1∙103 µM−2·s−1 | pH = 7 pH = 7.4 | [18,19] a |
7 | 2778 d | 2.78∙106 s−1 | |||
8 | 10 µM | 0.5 s−1 | [19] b | ||
9 | E(FAD/FADH•) = −127 E([2Fe-2S]) = 0 | 0.006 | 1∙103 µM−2·s−1 | pH = 7 pH = 7.4 | [18,19] a |
10 | 0.02 µM−1 | 103 s−1 | [15] b | ||
11 | E(FADH•/FADH2) = −31 E([2Fe-2S]) = 0 | 0.289 µM−1 | 1∙103 µM−2·s−1 | pH = 7 pH = 7.4 | [18,19] a |
12 | 0.02 µM−1 | 103 s−1 | [15] b | ||
13 | E(FAD/FADH•) = −127 E([2Fe-2S]) = 0 | 2.4∙10−4 e µM−1 | 1∙103 µM−2·s−1 | pH = 7 pH = 7.4 | [18,19] a |
14 | 250 µM | 10 s−1 | [15] b | ||
15 | E(FADH•/FADH2) = −31 E([2Fe-2S]) = 0 | 0.289 e µM−1 | 1∙103 µM−2·s−1 | pH = 7 pH = 7.4 | [18,19] a |
16 | 250 µM | 10 s−1 | [15] b | ||
Hydrogen peroxide (H2O2) production by Complex II | |||||
17 | E(O2/H2O2) = 690 E(FAD/FADH2) = −79 | 5.2∙1026 | 0.01 µM−1·s−1 | pH = 7 | [19] a |
Superoxide anion (O2∙−) production by the subcomplex SDHA/SDHB of SDH | |||||
18 | E(O2/O2∙−) = −160 E(FADH•/FADH2) = −31 | 6∙10−3 | 0.01 µM−1·s−1 | pH = 7 | [20] a [19] a |
19 | E(O2/O2∙−) = −160 E(FAD/FADH•) = −127 | 0.267 | 0.1 µM−1·s−1 | pH = 7 pH = 7.4 | [20] a [19] a |
20 | E(O2/O2∙−) = −160 E([3Fe-4S]) = 60 | 1.5∙10−4 | 1·10−3 µM−1·s−1 | pH = 7 pH = 7.4 | [20] a [17] a |
Accompanying reactions in the matrix and inner membrane | |||||
Superoxide anion dismutation in the mitochondrial matrix | |||||
21 | Vmax21 = 5.6∙104 µM·s−1 f Km21 = 50 µM | [21] d | |||
Efflux of hydrogen peroxide (H2O2) from the mitochondrial matrix to cytoplasm | |||||
22 | 30 s−1 | [22] c |
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Markevich, N.I.; Markevich, L.N. Mathematical Modeling of ROS Production and Diode-like Behavior in the SDHA/SDHB Subcomplex of Succinate Dehydrogenases in Reverse Quinol-Fumarate Reductase Direction. Int. J. Mol. Sci. 2022, 23, 15596. https://doi.org/10.3390/ijms232415596
Markevich NI, Markevich LN. Mathematical Modeling of ROS Production and Diode-like Behavior in the SDHA/SDHB Subcomplex of Succinate Dehydrogenases in Reverse Quinol-Fumarate Reductase Direction. International Journal of Molecular Sciences. 2022; 23(24):15596. https://doi.org/10.3390/ijms232415596
Chicago/Turabian StyleMarkevich, Nikolay I., and Lubov N. Markevich. 2022. "Mathematical Modeling of ROS Production and Diode-like Behavior in the SDHA/SDHB Subcomplex of Succinate Dehydrogenases in Reverse Quinol-Fumarate Reductase Direction" International Journal of Molecular Sciences 23, no. 24: 15596. https://doi.org/10.3390/ijms232415596