Naked mole rats suppress energy metabolism and modulate membrane cholesterol in chronic hypoxia.
Naked mole rats (NMRs) are mammalian champions of hypoxia tolerance that enter metabolic suppression to survive in low oxygen environments. Common physiological mechanisms used by animals to supress metabolic rate include downregulating energy metabolism (ATP supply) as well as ion pumps (primary cellular ATP consumers) A recent study in goldfish demonstrated that remodelling of membrane lipids may mediate these responses, but it is unknown if NMRs employ the same strategies; therefore, we aimed to test the hypotheses that these fossorial mammals: (i) downregulate the activity of key enzymes of glycolysis, TCA cycle, and b oxidation, (ii) inhibit sodium/potassium ATPase, and (iii) remodel membrane lipids in response to chronic hypoxia. We found that NMRs exposed to 11% oxygen for 4 weeks lower metabolic rate by 34% This suppression occurs concurrently with tissue specific 25 99% decreases in metabolic enzymes activities, a 77% decrease in brain sodium/potassium ATPase activity, and widespread changes in membrane cholesterol abundance. By reducing glycolytic and b oxidation fluxes, NMR decrease the supply of acetyl CoA to the tricarboxylic acid cycle. By contrast, there is a 94% upregulation of citrate synthase in the heart, possibly to support circulation, and thus oxygen supply to other organs. Taken together, these responses may reflect a coordinated physiological response to hypoxia, but a clear functional link between membrane remodelling and changes in enzyme activities could not be established. Nevertheless, this is the first demonstration that chronic in vivo exposure to hypoxia not only induces hypometabolism, but also results in a significant restructuring of membrane lipids in all NMR tissues.
American journal of physiology. Regulatory, integrative and comparative physiology