A Novel Metabolic Program Fuels Continued Anaerobic Glycolysis in the Hypoxia Tolerant Naked Mole-Rats

Survival strategies against the pathologies of low oxygen conditions that challenge the fundamentals of biological physiology are explored. Here within is described a novel redox shuttle that is utilized in the hypoxia-tolerant naked mole-rat, which utilizes a uniquely upregulated pulmonary gluconeogenic pathway to produce, from the bottom up, carbonyls that can yield ATP and pyruvate, which is capable of transporting redox potential to energy-demanding hypoxic organs. A multiomics analysis is conducted on hypoxic tissues, and several quantifications of key enzyme activities are provided. Interventions that block the transport of this redox shuttle are provided, and read-outs in terms of behavioral activity and cardiac parameters are provided. In conclusion, the naked mole-rat is shown to be host to a highly unique and novel pathway that provides for continued anaerobic glycolytic activity under hypoxia with implications for oncology, stroke, and other pathologies that witness hypoxic conditions.