Succinate-driven cardiac mitochondrial respiration aligns with whole-animal hypoxia-tolerance in African mole-rats

Abstract

Variations in environmental oxygen availability can induce oxidative stress in mammalian cells; episodes of hypoxia/re-oxygenation can be deleterious to cardiac function. Subterranean-living African naked mole-rats putatively experience repeated bouts of hypoxia/re-oxygenation in their natural habitat and are among the most hypoxia-tolerant mammals. To mitigate the potentially deleterious effects of frequent hypoxia/re-oxygenation exposure, naked mole-rats possess cardiac mitochondrial adaptations that may limit oxidative damage caused by fluctuating environmental oxygen levels. These include low respiratory flux through complex II (succinate dehydrogenase) of the mitochondrial electron transport system and robust cardiac reactive oxygen species (ROS) scavenging capacities. We hypothesized that these specializations are common traits in all hypoxia-tolerant African mole-rats. To test this hypothesis, we evaluated mitochondrial respiration and both ROS efflux and scavenging capabilities from naked mole-rats, six additional hypoxia-tolerant African mole-rat species, and hypoxia-intolerant mice (Mus musculus), rats (Rattus norvegicus; non-subterranean), and star-nosed moles (Condylura cristata; subterranean). We found a clear and inverse relationship between complex II-fuelled respiration of isolated mitochondria and hypoxia-tolerance across all species tested. Conversely, we found no relationship between hypoxia-tolerance and rates of complex I-fuelled respiration, H2O2 efflux (with any substrate), or mitochondrial H2O2 scavenging capacity. Our results suggest that downregulating the catalytic capacity of cardiac mitochondrial complex II may be an adaptation that supports systemic hypoxia-tolerance in African mole-rats.