Naked mole-rats (NMRs) are mammalian champions of hypoxia tolerance that enter metabolic suppression to survive in low oxygen environments. Common physiological mechanisms used by animals to suppress metabolic rate include downregulating energy metabolism (ATP supply) as well as ion pumps (primary cellular ATP consumers). A recent goldfish study demonstrated that remodeling of membrane lipids may mediate these responses, but it is unknown if NMR employs the same strategies; therefore, we aimed to test the hypotheses that these fossorial mammals 1) downregulate the activity of key enzymes of glycolysis, tricarboxylic acid (TCA) cycle, and β-oxidation, 2) inhibit sodium-potassium-ATPase, and 3) alter membrane lipids in response to chronic hypoxia. We found that NMRs exposed to 11% oxygen for 4 wk had a lower metabolic rate by 34%. This suppression occurs concurrently with tissue-specific 25-99% decreases in metabolic enzymes activities, a 77% decrease in brain sodium/potassium-ATPase activity, and widespread changes in membrane cholesterol abundance. By reducing glycolytic and β-oxidation fluxes, NMRs decrease the supply of acetyl-CoA to the TCA cycle. By contrast, there is a 94% upregulation of citrate synthase in the heart, possibly to support circulation and thus oxygen supply to other organs. Taken together, these responses may reflect a coordinated physiological response to hypoxia, but a clear functional link between changes in membrane composition and enzyme activities could not be established. Nevertheless, this is the first demonstration that hypometabolic NMRs alter the lipid composition of their membranes in response to chronic in vivo exposure to hypoxia.

中文翻译：

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裸鼹鼠抑制能量代谢并调节慢性缺氧中的膜胆固醇。

裸鼹鼠 (NMR) 是耐缺氧的哺乳动物，它们进入代谢抑制以在低氧环境中生存。动物用来抑制代谢率的常见生理机制包括下调能量代谢（ATP 供应）以及离子泵（主要细胞 ATP 消费者）。最近的一项金鱼研究表明，膜脂的重塑可能会介导这些反应，但不知道 NMR 是否采用相同的策略；因此，我们旨在检验以下假设：这些化石哺乳动物 1) 下调糖酵解、三羧酸 (TCA) 循环和 β-氧化的关键酶的活性，2) 抑制钠-钾-ATP 酶，以及 3) 改变膜脂以应对慢性缺氧。我们发现 NMR 暴露于 11% 的氧气 4 周后，其代谢率降低了 34%。这种抑制与组织特异性代谢酶活性降低 25-99%、脑钠/钾-ATP 酶活性降低 77% 以及膜胆固醇丰度的广泛变化同时发生。通过减少糖酵解和 β-氧化通量，NMR 减少了 TCA 循环中乙酰辅酶 A 的供应。相比之下，心脏中的柠檬酸合酶上调了 94%，这可能是为了支持循环，从而为其他器官提供氧气。总之，这些反应可能反映了对缺氧的协调生理反应，但无法建立膜成分变化与酶活性之间的明确功能联系。尽管如此，这是首次证明低代谢 NMR 改变其膜的脂质组成以响应体内慢性缺氧暴露。