Hypoxia is one of the strongest environmental drivers of cellular and physiological adaptation. Although most mammals are largely intolerant of hypoxia, some specialized species have evolved mitigative strategies to tolerate hypoxic niches. Among the most hypoxia-tolerant mammals are naked mole-rats (Heterocephalus glaber), a eusocial species of subterranean rodent native to eastern Africa. In hypoxia, naked mole-rats maintain consciousness and remain active despite a robust and rapid suppression of metabolic rate, which is mediated by numerous behavioural, physiological and cellular strategies. Conversely, hypoxia-intolerant mammals and most other hypoxia-tolerant mammals cannot achieve the same degree of metabolic savings while staying active in hypoxia and must also increase oxygen supply to tissues, and/or enter torpor. Intriguingly, recent studies suggest that naked mole-rats share many cellular strategies with non-mammalian vertebrate champions of anoxia tolerance, including the use of alternative metabolic end-products and potent pH buffering mechanisms to mitigate cellular acidification due to upregulation of anaerobic metabolic pathways, rapid mitochondrial remodelling to favour increased respiratory efficiency, and systemic shifts in energy prioritization to maintain brain function over that of other tissues. Herein, I discuss what is known regarding adaptations of naked mole-rats to a hypoxic lifestyle, and contrast strategies employed by this species to those of hypoxia-intolerant mammals, closely related African mole-rats, other well-studied hypoxia-tolerant mammals, and non-mammalian vertebrate champions of anoxia tolerance. I also discuss the neotenic theory of hypoxia tolerance – a leading theory that may explain the evolutionary origins of hypoxia tolerance in mammals – and highlight promising but underexplored avenues of hypoxia-related research in this fascinating model organism.

Naked mole rats (NMRs) are among the most hypoxia-tolerant mammals. Other species respond to hypoxia by either escaping the hypoxic environment or drastically decreasing behavioural activity and body temperature (T_b) to conserve energy. However, NMRs rarely leave their underground burrows, which are putatively hypoxic and thermally stable near the NMRs' preferredT_b. Therefore, we asked whether NMRs are able to employ behavioural and thermoregulatory strategies in response to hypoxia despite their need to remain active and the minimal thermal scope in their burrows. We exposed NMRs to progressively deeper levels of hypoxia (from 21 to 0% O₂) while measuring their behaviour andT_b. Behavioural activity decreased 40–60% in hypoxia andT_bdecreased slightly in moderate hypoxia (5–9%) and then further with deeper hypoxia (3% O₂). However, even at 3% O₂NMRs remained somewhat active and warm, and continued to explore their environment. Remarkably, NMRs were active for greater than 90 s in acute anoxia andT_band metabolic rate decreased rapidly. We conclude that NMRs are adapted to remain awake and functional even at the extremes of their hypoxia-tolerance. This adaptation likely reflects variable and challenging levels of environmental hypoxia in the natural habitat of this species.

In severe hypoxia, most vertebrates increase anaerobic energy production, which results in the development of a metabolic acidosis and an O₂ debt that must be repaid during reoxygenation. Naked mole rats (NMRs) are among the most hypoxia-tolerant mammals, capable of drastically reducing their metabolic rate in acute hypoxia; while staying active and alert. We hypothesized that a key component of remaining active is an increased reliance on anaerobic metabolism during severe hypoxia. To test this hypothesis, we exposed NMRs to progressive reductions in inspired O₂ (9 to 3% O₂) followed by reoxygenation (21% O₂) and measured breathing frequency, heart rate, behavioural activity, body temperature, metabolic rate, and also metabolic substrates and pH in blood and tissues. We found that NMRs exhibit robust metabolic rate depression in acute hypoxia, accompanied by declines in all physiological and behavioural variables examined. However, blood and tissue pH were unchanged and tissue [ATP] and [phosphocreatine] were maintained. Naked mole rats increased their reliance on carbohydrates in hypoxia, and glucose was mobilized from the liver to the blood. Upon reoxygenation NMRs entered into a coma-like state for∼15-20 mins during which metabolic rate was negligible and body temperature remained suppressed. However, an imbalance in the rates at which V̇_O2 and V̇_CO2 returned to normoxic levels during reoxygenation hint at the possibility that NMRs do utilize anaerobic metabolism during hypoxia but have a tissue and/or blood buffering capacity that mask typical markers of metabolic acidosis, and prioritize the synthesis of glucose from lactate during recovery.

Naked mole-rats are among the most hypoxia-tolerant mammals. During hypoxia, their body temperature (T_b) decreases via unknown mechanisms to conserve energy. In small mammals, non-shivering thermogenesis in brown adipose tissue (BAT) is critical to T_b regulation; therefore, we hypothesize that hypoxia decreases naked mole-rat BAT thermogenesis. To test this, we measure changes in T_b during normoxia and hypoxia (7% O₂; 1–3 h). We report that interscapular thermogenesis is high in normoxia but ceases during hypoxia, and T_b decreases. Furthermore, in BAT from animals treated in hypoxia, UCP1 and mitochondrial complexes I-V protein expression rapidly decrease, while mitochondria undergo fission, and apoptosis and mitophagy are inhibited. Finally, UCP1 expression decreases in hypoxia in three other social African mole-rat species, but not a solitary species. These findings suggest that the ability to rapidly down-regulate thermogenesis to conserve oxygen in hypoxia may have evolved preferentially in social species.