Naked mole rat TRF1 safeguards glycolytic capacity and telomere replication under low oxygen

The naked mole rat (NMR), a long-lived and cancer resistant rodent, is highly resistant to hypoxia. Here, using robust cellular models wherein the mouse telomeric protein TRF1 is substituted by the NMR TRF1 or its mutant forms, we show that TRF1 supports maximal glycolytic capacity under low oxygen, shows increased nuclear localization and association with telomeres, and protects telomeres from replicative stress. We pinpoint this evolutionary gain of metabolic function to specific amino acid changes in the homodimerization domain of this protein. We further find that NMR TRF1 accelerates telomere shortening. These findings reveal an evolutionary strategy to adapt telomere biology for metabolic control under an extreme environment. mRNA profiles of tMEF cells (transformed mouse embryonic fibroblasts), cultured in normoxia and hypoxia conditions, wherein the mouse telomeric protein TRF1 is substituted by the NMR TRF1 or its mutants forms: mutGLAD (Glu69Lys, Val70Ala, and Ala75Thr), mutTIN (Ala105Thr) or both mutGLAD/TIN. The experiments were performed in duplicate using the sequencer Illumina NovaSeq 6000.