Some unique vertebrates are able to survive prolonged hypoxia via strong metabolic suppression. We have investigated potential mechanisms used by goldfish and naked mole-rats (NMR) to support this essential hypometabolic response. Key enzymes of energy metabolism and Na/K-ATPase were examined together with membrane composition because membrane remodeling is known to regulate trans-membrane proteins in vitro. The effects of 4 weeks of hypoxia on metabolic rate, energy metabolism, Na/K-ATPase and membrane composition were quantified in different tissues. Common responses of both species were: (1) 34-74% decrease in metabolic rate; (2) large changes in membrane cholesterol (90% increase in muscle; 53% decrease in liver); and (3) 40-77% decrease in brain Na/K-ATPase activity. Brain cholesterol also decreased by 26% in NMR, but it remained unchanged in goldfish. NMRs downregulated flux capacities for glycolysis, beta-oxidation and tricarboxylic acid cycle in all tissues except for beta-oxidation in brain. Enzymes of goldfish energy metabolism responded with more variability and they were tissue-specific. This study shows for the first time that chronic hypoxia can remodel membrane lipids in vivo. Changing membrane lipids could be a novel mechanism to promote metabolic suppression, but a clear functional link between membrane restructuring and hypometabolism could not be established. A common membrane signal regulating the inhibition of ion pumps and ion channels could be an exquisite way to preserve the balance between ATP supply and demand in the hypometabolic state, and it could serve as a neuroprotective mechanism in the brain.