Lactate inhibits naked mole-rat cardiac mitochondrial respiration

In aerobic conditions, the proton-motive force drives oxidative phosphorylation (OXPHOS) and the conversion of ADP to ATP. In hypoxic environments, OXPHOS is impaired, resulting in energy shortfalls and the accumulation of protons and lactate. This results in cellular acidification, which may impact the activity and/or integrity of mitochondrial enzymes and in turn negatively impact mitochondrial respiration and thus aerobic ATP production. Naked mole-rats (NMRs) are among the most hypoxia-tolerant mammals and putatively experience intermittent hypoxia in their underground burrows. However, if and how NMR cardiac mitochondria are impacted by lactate accumulation in hypoxia is unknown. We predicted that lactate alters mitochondrial respiration in NMR cardiac muscle. To test this, we used high-resolution respirometry to measure mitochondrial respiration in permeabilized cardiac muscle fibres from NMRs exposed to 4 h of in vivo normoxia (21% O₂) or hypoxia (7% O₂). We found that: (1) cardiac mitochondria cannot directly oxidize lactate, but surprisingly, (2) lactate inhibits mitochondrial respiration, and (3) decreases complex IV maximum respiratory capacity. Finally, (4) in vivo hypoxic exposure decreases the magnitude of lactate-mediated inhibition of mitochondrial respiration. Taken together, our results suggest that lactate may retard electron transport system function in NMR cardiac mitochondria, particularly in normoxia, and that NMR hearts may be primed for anaerobic metabolism.