Naked mole-rats reduce the expression of ATP-dependent but not ATP-independent heat shock proteins in acute hypoxia

Naked mole-rats are one of the most hypoxia-tolerant mammals identified, and putatively experience intermittent and severe hypoxia in their underground burrows. Systemic physiological adaptions to hypoxia have begun to be investigated in this species; however, the cellular adaptations that underlie this tolerance remain poorly understood. Hypoxia compromises cellular energy production, and the maintenance of protein integrity when ATP generation is limited poses a major challenge. Heat shock proteins (HSPs) are cellular chaperones that are cytoprotective during hypoxia, and we hypothesized that their expression would increase during acute hypoxia in naked mole-rats. To test this hypothesis, we used qPCR and western blot approaches to measure changes in gene and protein expression, respectively, of HSP27, HSP40, HSP70 and HSP90 in the brain, heart, liver and temporalis muscle from naked mole-rats following exposure to normoxia (21% O₂) or hypoxia (7% O₂ for 4, 12 or 24 h). Contrary to our expectations, we observed significant global reductions of ATP-dependent HSP70 and HSP90 (83% and 78%, respectively) after 24 h of hypoxia. Conversely, the expression of ATP-independent HSP27 and HSP40 proteins remained constant throughout the 24-h hypoxic treatment in brain, heart and muscle. However, with prolonged hypoxia (24 h), the expression of Hsp27 and Hsp40 genes in these tissues was also reduced, suggesting that the protein expression of these chaperones may also eventually decrease in hypoxia. These results suggest that energy conservation is prioritized over cytoprotective protein chaperoning in naked mole-rat tissues during acute hypoxia. This unique adaptation may help naked mole-rats to minimize energy expenditure while still maintaining proteostasis in hypoxia.