IN VITRO MODELS TO STUDY HYPOXIA-RESISTANCE IN THE NAKED MOLE-RAT

Naked mole-rats (NM-Rs) show extraordinary tolerance to hypoxia in vivo, yet the cellular and molecular mechanisms underlying this trait remain poorly understood. To address this, I established and characterized induced neuronal and primary astrocytic NM-R cultures for comparative studies with mouse. Functional experiments revealed increased survival in both NM-R cell types upon oxygen deprivation, with the effect being more pronounced in astrocytes. Preliminary proteomic profiling under normoxia and hypoxia revealed divergent responses: while mouse astrocytes mounted a broad HIF-1α–driven upregulation of glycolysis, translation, proteasome and stress pathways, the NM-R astrocytic proteome remained remarkably stable and displayed only selective changes. These included differential modulation of proteostasis machinery, as well as differences in calcium handling and secretory pathways. Complementary work in NM-R fibroblasts identified OPA1 as a potential orchestrator of hypoxia resilience via mitochondrial adaptation. NM-Rs not only express higher levels of this protein but also harbor a unique isoform predicted to stabilize mitochondrial cristae junctions and potentially delay initiation of cell death under hypoxic conditions. Together, these findings highlight cellular and mitochondrial strategies contributing to NM-R hypoxia resilience and point to potential targets for conditions associated with oxygen deprivation.