Naked mole-rat brain mitochondria tolerate in vitro ischaemia

Naked mole-rats (NMRs; Heterocephalus glaber) are among the most hypoxia-tolerant mammals. There is evidence that the NMR brain tolerates in vitro hypoxia and NMR brain mitochondria exhibit functional plasticity following in vivo hypoxia; however, if and how these organelles tolerate ischaemia and how ischaemic stress impacts mitochondrial energetics and redox regulation is entirely unknown. We hypothesized that mitochondria fundamentally contribute to in vitro ischaemia resistance in the NMR brain. To test this, we treated NMR and CD-1 mouse cortical brain sheets with an in vitro ischaemic mimic and evaluated mitochondrial respiration capacity and redox regulation following 15 or 30 min of ischaemia or ischaemia/reperfusion (I/R). We found that, relative to mice, the NMR brain largely retains mitochondrial function and redox balance post-ischaemia and I/R. Specifically: (i) ischaemia reduced complex I and II-linked respiration ∼50-70% in mice, vs. ∼20-40% in NMR brain, (ii) NMR but not mouse brain maintained relatively steady respiration control ratios and robust mitochondrial membrane integrity, (iii) electron leakage post-ischaemia was lesser in NMR than mouse brain and NMR brain retained higher coupling efficiency, and (iv) free radical generation during and following ischaemia and I/R was lower from NMR brains than mice. Taken together, our results indicate that NMR brain mitochondria are more tolerant of ischaemia and I/R than mice and retain respiratory capacity while avoiding redox derangements. Overall, these findings support the hypothesis that hypoxia-tolerant NMR brain is also ischaemia-tolerant and suggest that NMRs may be a natural model of ischaemia tolerance in which to investigate evolutionarily derived solutions to ischaemic pathology. KEY POINTS: Ischaemia is highly deleterious to the mammalian brain and this damage is largely mediated by mitochondrial dysfunction. Naked mole-rats are among the most hypoxia-tolerant mammals and their brain tolerates ischaemia ex vivo, but the impact of ischaemia on mitochondrial function is unknown. Naked mole-rat but not mouse brain mitochondria retain respiratory capacity and membrane integrity following ischaemia or ischaemia/reperfusion. Differences in free radical management and respiratory pathway control between species may mediate this tolerance. These results help us understand how natural models of hypoxia tolerance also tolerate ischaemia in the brain.