We have developed a simple model that captures the behavior of mitochondrial respiration, ATP synthesis, and ROS production. We then used the model to explain experimental observations of the non-ohmic rise in the passive proton leak rate at high membrane potential as well as the dependence of the proton leak rate on increased ROS production. We also used the model to investigate mitochondrial responses to glycolytic and calcium inputs. In agreement with experimental observations in the literature, our model is capable of capturing mitochondrial behavior, such as the non-ohmic rise in the passive proton leak at high membrane potentials due to uncoupling proteins and the effects of superoxide generating systems like xanthine and xanthine oxidase. In its current state, our model does not support the idea that the pool of available scavenging enzymes is entirely oxidized (or deactivated) under high glycolytic input, thus leading to oxidative stress. However, our model does provide evidence that ROS is saturated under high glycolytic input, thus debilitating ROS signaling. Investigation of downstream ROS signaling targets is one direction for future work, while another is to incorporate more details of ROS production from the electron transport chain to investigate conditions leading to high ROS levels. The ROS saturation could indicate that ROS signaling is less efficient when glucose levels are abnormally high. There may be a need to include more feedback mechanisms, such as the dynamics of the mitochondrial network (fusion and fission of mitochondria) and the effect of insulin levels on nutrient uptake and suppression of lipolysis.
