Models

Competing models of mitochondrial energy metabolism in the heart are highly disputed. In addition, the mechanisms of reactive oxygen species (ROS) production and scavenging are not well understood. To deepen our understanding of these processes, a computer model was developed to integrate the biophysical processes of oxidative phosphorylation and ROS generation. The model was calibrated with experimental data obtained from isolated rat heart mitochondria subjected to physiological conditions and workloads. Model simulations show that changes in the quinone pool redox state are responsible for the apparent inorganic phosphate activation of complex III. Model simulations predict that complex III is responsible for more ROS production during physiological working conditions relative to complex I. However, this relationship is reversed under pathological conditions. Finally, model analysis reveals how a highly reduced quinone pool caused by elevated levels of succinate is likely responsible for the burst of ROS seen during reperfusion after ischemia.

Model diagram. The model consists of descriptors for substrate oxidation, the electron transport chain, oxidative phosphorylation, and the potassium/proton exchanger (KHE). The substrate oxidation descriptor is an empirical function characterizing NADH and FADH2 production. The electron transport chain consists of NADH-ubiquinone oxidoreductase (CI), succinate dehydrogenase (CII), ubiquinol cytochrome coxidoreductase (CIII), and cytochrome c oxidase (CIV). The oxidative phosphorylation components are ATP synthase (F1FO), adenine nucleotide translocase (ANT), and the inorganic phosphate carrier (PiC). The number of protons required to produce one ATP molecule (n) by F1FO is set to 2.67. An extra proton enters mitochondria through the PiC and ANT, which raises the H:ATP ratio to 3.67 as seen from outside the mitochondria.