The African naked mole-rats’ (Heterocephalus glaber) social and subterranean lifestyle
generates a hypoxic niche. Under experimental conditions naked mole-rats tolerate hours of
extreme hypoxia and survive 18 minutes of total oxygen deprivation (anoxia) without apparent
injury. During anoxia the naked mole-rat switches to anaerobic metabolism fueled by fructose
which is actively accumulated and metabolized to lactate in the brain. Global expression of the
GLUT5 fructose transporter and high levels of ketohexokinase (KHK) were identified as
molecular signatures of fructose metabolism. Fructose-driven glycolytic respiration in naked
mole-rat tissues avoids feedback inhibition of glycolysis via phosphofructokinase, supporting
viability. The metabolic rewiring of glycolysis can circumvent the normally lethal effects of
oxygen-deprivation a mechanism that could be harnessed to minimize hypoxic damage in human
disease.
