Mechanisms and mathematical modelling of ROS production by the mitochondrial electron transport chain

Reactive oxygen species (ROS) are recognised both as damaging molecules and intracellular signalling entities. In addition to its role in ATP generation, the mitochondrial electron transport chain (ETC) constitutes a relevant source of mitochondrial ROS, in particular during pathological conditions. Mitochondrial ROS homeostasis depends on species- and site-dependent ROS production, their bioreactivity, diffusion, and scavenging. However, our quantitative understanding of mitochondrial ROS homeostasis has thus far been hampered by technical limitations, including lack of truly site- and/or ROS-specific reporter molecules. In this context, the use of computational models is of great value to complement and interpret empirical data, as well as to predict variables that are difficult to assess experimentally. During the last decades, various mechanistic models of ETC-mediated ROS production have been developed. Although these often-complex models have generated novel insights, their parameterisation, analysis, and integration with other computational models is not straightforward. In contrast, phenomenological (sometimes termed "minimal") models use a relatively small set of equations to describe empirical relationship(s) between ROS-related and other parameters, and generally aim to explore system behaviour and generate hypotheses for experimental validation. In this review, we first discuss ETC-linked ROS homeostasis and introduce various detailed mechanistic models. Next, we present how bioenergetic parameters (e.g. NADH/NAD ratio, mitochondrial membrane potential) relate to site-specific ROS production within the ETC and how these relationships can be used to design minimal models of ROS homeostasis. Finally, we illustrate how minimal models have been applied to explore pathophysiological aspects of ROS.