Mathematical Model of Electron Transfer and the Formation of Reactive Oxygen Species in Mitochondrial Complex II
The main goal of this work is 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, necroptosis). On the basis of the published experimental data, a kinetic scheme of electron transfer from succinate to coenzyme Q through a number of redox centers localized in subcomplexes A, B, C, D of complex II was developed. 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 (<inline-formula><inline-graphic href="BioMem1905007Markevich-m2" xmlns:xlink="http://www.w3.org/1999/xlink"></inline-graphic></inline-formula>) and hydroperoxide (H<sub>2</sub>O<sub>2</sub>). The analysis of the mathematical model show that the bell-shaped kinetics of the ROS formation observed experimentally at a micromolar range of succinate concentrations (from tens to hundreds micromols of succinate) upon inhibition of complex III is inherent only in two potential generators of ROS, FADH2 and FADH. At the same time, the kinetics of ROS formation by Fe-S redox centers of complex II, as well as ubiquinone-binding center, is close to sigmoidal; apparently, these redox centers make a minor contribution to the overall production of ROS by complex II.