Abstract

Reactive oxygen species (ROS) have been implicated in disorders ranging from neurodegenerative diseases to diabetes to heart disease. In cardiac myocytes mitochondria represent the predominant source of ROS, specifically complexes I and III. The model presented here endeavors to explore and elucidate the modulation of electron transport chain ROS production under state 3 versus state 4 respiration and the role of succinate as a substrate. A mechanistic complex III model was developed, driven by redox potential differences between adjacent redox centers. This model shows that ROS production increases exponentially with membrane potential when in state 4. Because the mechanism of ROS production from complex I remains unknown, a more general thermodynamic model was used to describe the influence of NADH/NAD+ and ubiquinone/ubiquinol redox potentials on complex I-derived ROS release. This release occurs in the presence of NADH and succinate, leading to a highly reduced ubiquinone pool, displaying the highest ROS production flux in state 4. Overall, total ROS production is moderate in state 3 and increases substantially under state 4 conditions. The ROS production model was combined with a minimal model of ROS scavenging. Since scavenging systems rely on the reduced form of NADPH, scavenging capacity decreases as the cellular environment becomes more oxidized. When the cellular redox status is modified by increasing mitochondrial inner membrane uncoupling, simulations with the combined model of ROS production and scavenging show that ROS levels initially decline as production drops off with decreasing membrane potential and then increase as the mitochondria become more oxidized and scavenging capacity is exhausted. Hence this mechanistic model of ROS production demonstrates how ROS levels are controlled by the cellular redox environment in agreement with the Redox-optimized ROS Balance hypothesis.

Full Text
Published version (Free)

Talk to us

Join us for a 30 min session where you can share your feedback and ask us any queries you have

Schedule a call