Enhanced mitochondrial buffering prevents Ca overload in naked mole-rat brain.

Deleterious Ca accumulation is central to hypoxic cell death in the brain of most mammals. Conversely, hypoxia-mediated increases in cytosolic Ca are retarded in hypoxia-tolerant naked mole-rat brain. We hypothesized that naked mole-rat brain mitochondria have an enhanced capacity to buffer exogenous Ca and examined Ca handling in naked mole-rat cortical tissue. We report that naked mole-rat brain mitochondria buffer >2-fold more exogenous Ca than mouse brain mitochondria, and that the half-maximal inhibitory concentration (IC) at which Ca inhibits aerobic oxidative phosphorylation is >2-fold higher in naked mole-rat brain. The primary driving force of Ca uptake is the mitochondrial membrane potential (Δψ), and the IC at which Ca decreases Δψ is ∼4-fold higher in naked mole-rat than mouse brain. The ability of naked mole-rat brain mitochondria to safely retain large volumes of Ca may be due to ultrastructural differences that support the uptake and physical storage of Ca in mitochondria. Specifically, and relative to mouse brain, naked mole-rat brain mitochondria are larger and have higher crista density and increased physical interactions between adjacent mitochondrial membranes, all of which are associated with improved energetic homeostasis and Ca management. We propose that excessive Ca influx into naked mole-rat brain is buffered by physical storage in large mitochondria, which would reduce deleterious Ca overload and may thus contribute to the hypoxia and ischaemia-tolerance of naked mole-rat brain. KEY POINTS: Unregulated Ca influx is a hallmark of hypoxic brain death; however, hypoxia-mediated Ca influx into naked mole-rat brain is markedly reduced relative to mice. This is important because naked mole-rat brain is robustly tolerant against in vitro hypoxia, and because Ca is a key driver of hypoxic cell death in brain. We show that in hypoxic naked mole-rat brain, oxidative capacity and mitochondrial membrane integrity are better preserved following exogenous Ca stress. This is due to mitochondrial buffering of exogenous Ca and is driven by a mitochondrial membrane potential-dependant mechanism. The unique ultrastructure of naked mole-rat brain mitochondria, as a large physical storage space, may support increased Ca buffering and thus hypoxia-tolerance.