Enhanced mitochondrial buffering prevents Ca 2+ overload in naked mole-rat brain.

Deleterious Ca 2+ accumulation is central to hypoxic cell death in the brain of most mammals. Conversely, hypoxia-mediated increases in cytosolic Ca 2+ 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 2+ and examined Ca 2+ handling in naked mole-rat cortical tissue. We report that naked mole-rat brain mitochondria buffer >2-fold more exogenous Ca 2+ than mouse brain mitochondria, and that the half-maximal inhibitory concentration (IC 50 ) at which Ca 2+ inhibits aerobic oxidative phosphorylation is >2-fold higher in naked mole-rat brain. The primary driving force of Ca 2+ uptake is the mitochondrial membrane potential (Δψ m ), and the IC 50 at which Ca 2+ decreases Δψ m 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 2+ may be due to ultrastructural differences that support the uptake and physical storage of Ca 2+ 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 2+ management. We propose that excessive Ca 2+ influx into naked mole-rat brain is buffered by physical storage in large mitochondria, which would reduce deleterious Ca 2+ overload and may thus contribute to the hypoxia and ischaemia-tolerance of naked mole-rat brain. KEY POINTS: Unregulated Ca 2+ influx is a hallmark of hypoxic brain death; however, hypoxia-mediated Ca 2+ 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 2+ 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 2+ stress. This is due to mitochondrial buffering of exogenous Ca 2+ 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 2+ buffering and thus hypoxia-tolerance.