Glucose has long been considered the primary fuel source for the brain. However, glucose levels fluctuate in the brain during sleep or circuit activity, posing major metabolic stress. Here, we demonstrate that the mammalian brain uses pyruvate as a fuel source, and pyruvate can support neuronal viability in the absence of glucose. Nerve terminals are sites of metabolic vulnerability, and we show that mitochondrial pyruvate uptake is a critical step in oxidative ATP production in hippocampal terminals. We find that the mitochondrial pyruvate carrier is post-translationally modified by lysine acetylation, which, in turn, modulates mitochondrial pyruvate uptake. Our data reveal that the mitochondrial pyruvate carrier regulates distinct steps in neurotransmission, namely, the spatiotemporal pattern of synaptic vesicle release and the efficiency of vesicle retrieval—functions that have profound implications for synaptic plasticity. In summary, we identify pyruvate as a potent neuronal fuel and mitochondrial pyruvate uptake as a critical node for the metabolic control of neurotransmission in hippocampal terminals.

中文翻译：

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线粒体丙酮酸转运调节突触前代谢和神经传递


长期以来，葡萄糖一直被认为是大脑的主要燃料来源。然而，在睡眠或回路活动期间，大脑中的葡萄糖水平会波动，构成严重的代谢压力。在这里，我们证明了哺乳动物大脑使用丙酮酸作为燃料来源，而丙酮酸可以在没有葡萄糖的情况下支持神经元活力。神经末梢是代谢脆弱的部位，我们表明线粒体丙酮酸摄取是海马末梢氧化 ATP 产生的关键步骤。我们发现线粒体丙酮酸载体通过赖氨酸乙酰化进行翻译后修饰，这反过来又调节线粒体丙酮酸摄取。我们的数据显示，线粒体丙酮酸载体调节神经传递的不同步骤，即突触小泡释放的时空模式和囊泡恢复的效率——这些功能对突触可塑性具有深远的影响。总之，我们将丙酮酸确定为一种有效的神经元燃料，线粒体丙酮酸摄取是海马末梢神经传递代谢控制的关键节点。