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Maintaining energy balance in hypoxia-tolerant brains

Most mammalian brains are exquisitely sensitive to fluctuations in oxygen availability (i.e., to hypoxia). Brain cells have a high metabolic demand and are dependant on aerobic metabolic processes. When oxygen is limited, brain cells typically don’t have enough energy to maintain plasma membrane ion gradients, which results in electrical hyper-excitability, rundown of cellular ATP supplies, and eventually, cell death. However, the brains of hypoxia-tolerant mammals are able to survive periods of severe hypoxia, usually by decreasing energy demands to support a hypometabolic state. For example, naked mole-rats decrease their whole animal metabolic rate in severe hypoxia (below, panel A) but maintain brain [ATP] (panel B), suggesting that energy balance is maintained in brain, despite robust systemic hypometabolism. This is presumably supported by a substantial decrease in mitochondrial metabolism in brain tissue (panel C), combined with increasing the efficiency of mitochondrial respiration (panel D).

Hypometabolism during hypoxia in naked mole-rat brain appears to be regional as the activity of the Na-K-ATPase (which maintains cellular membrane potential and is thus a reasonable proxy for overall cellular metabolism in electrically-active cells), decreases in the large forebrain of naked mole-rats following in vivo hypoxic exposure, but is unchanged in the brainstem, and increases in the cerebellum. This suggests that the impact of hypoxia on the energy regulation of a hypoxia-tolerant mammalian brain is complex and varied.

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Other Pamenter Lab research interests: Hypoxia, Control of Breathing, Mitochondrial Energetics.