Mitochondrial physiology in cardiac muscle of deer mice native to high altitude

High-altitude environments present a significant challenge to endotherms, where hypoxia can constrain aerobic metabolism but low temperatures amplify the metabolic demands for thermogenesis. Circulatory O₂ delivery is essential for supporting aerobic metabolism, but it is unclear whether functional changes in cardiac mitochondria help high-altitude natives cope with cold hypoxia. We examined this issue in deer mice (Peromyscus maniculatus). Mice from populations native to high altitude and low altitude were born and raised in captivity, and adults from each population were acclimated to warm (25°C) normoxia or cold (5°C) hypoxia (∼12 kPa O₂). Mitochondrial respiration, reactive oxygen species (ROS) generation, metabolic and antioxidant enzyme activities, and oxidative stress markers were measured in left and right ventricle tissues. Respiratory capacities for oxidative phosphorylation and electron transport were similar between populations and unaffected by acclimation environment, as were activities of citrate synthase and cytochrome oxidase. However, lactate dehydrogenase activity increased in cold hypoxia and was greater in high-altitude mice than in low-altitude mice, probably to augment capacities for lactate oxidation. Mitochondrial ROS generation was lower in high-altitude mice, as measured both ex vivo in ventricle tissues and in vivo using MitoB. This was at least partly due to increased intra-mitochondrial ROS consumption, because population differences in mitochondrial ROS emission were abolished by auranofin (a thioredoxin reductase inhibitor). Consistent with these differences, high-altitude mice had less lipid peroxidation and protein carbonylation in ventricle tissue. These findings suggest that high-altitude adaptation has augmented mitochondrial ROS consumption pathways to support cardiac function in cold hypoxia. KEY POINTS: Deer mice native to high altitude somehow overcome the dual challenge of hypoxia, which constrains aerobic metabolism, and low temperatures, which increase demands for thermogenesis. We observed two key functional changes in cardiac mitochondria that probably help high-altitude mice overcome these challenges. High-altitude mice had increased lactate dehydrogenase activity in left and right ventricles to enhance the capacity for lactate oxidation. High-altitude mice exhibited lower mitochondrial reactive oxygen species (ROS) generation, probably due to enhanced intra-mitochondrial ROS consumption, and less oxidative stress. These results suggest that evolved changes in cardiac ROS management help overcome the challenges at high altitude.