Mathematical Model of Electron Transfer and Formation of Reactive Oxygen Species in Mitochondrial Complex II

Abstract—

The main goal of this work was a quantitative analysis of the kinetics of the formation of reactive oxygen species (ROS) by complex II of the mitochondrial respiratory chain. For this purpose, a mathematical model was developed for modeling and experimental studies of changes in mitochondria associated with ROS-induced activation of signaling pathways of cell death (apoptosis, necrosis, and necroptosis). A kinetic scheme of electron transfer from succinate to coenzyme Q through a number of redox centers localized in subcomplexes A, B, C, and D of complex II was developed on the basis of published experimental data. The mathematical model corresponding to the kinetic scheme is a system of 17 ordinary differential equations that describes both the concentration of oxidized and reduced states of various electron carriers and the electron flows in complex II, leading to the formation of ROS, superoxide (${\text{O}}_{2}^{{\centerdot - }}$) and hydroperoxide (H₂O₂). The results of analysis of the mathematical model have shown that the bell-shaped kinetics of the ROS formation observed experimentally at a micromolar range of succinate concentrations (from tens to hundreds micromoles of succinate) in the presence of the inhibitors of complex III was an inherent property of only flavin adenine dinucleotide (FADH2) and flavin adenine dinucleotide radical (FADH^∙), two potential generators of ROS. At the same time, ROS formation by the Fe–S redox centers of complex II, as well as ubiquinone-binding center exhibited about sigmoidal kinetics; apparently, these redox centers make a minor contribution to the overall production of ROS by complex II upon the inhibition of complex III.