Abstract：
Neuronal activity is an energy-intensive process that is largely sustained by instantaneous fuel utilization and ATP synthesis. However, how neurons couple ATP synthesis rate to fuel availability is largely unknown. Here, we demonstrate that the metabolic sensor enzyme O-linked N-acetyl glucosamine (O-GlcNAc) transferase regulates neuronal activity-driven mitochondrial bioenergetics in hippocampal and cortical neurons. We show that neuronal activity upregulates O-GlcNAcylation in mitochondria. Mitochondrial O-GlcNAcylation is promoted by activity-driven glucose consumption, which allows neurons to compensate for high energy expenditure based on fuel availability. To determine the proteins that are responsible for these adjustments, we mapped the mitochondrial O-GlcNAcome of neurons. Finally, we determine that neurons fail to meet activity-driven metabolic demand when O-GlcNAcylation dynamics are prevented. Our findings suggest that O-GlcNAcylation provides a fuel-dependent feedforward control mechanism in neurons to optimize mitochondrial performance based on neuronal activity. This mechanism thereby couples neuronal metabolism to mitochondrial bioenergetics and plays a key role in sustaining energy homeostasis.
摘要：
神经元活动是一个能量密集型过程，主要由瞬时燃料利用和ATP合成维持。然而,神经元如何将ATP合成速率与燃料的可用性耦合在很大程度上是未知的。这里,我们证明了代谢传感器酶O连接的N-乙酰葡糖胺（O-GlcNAc）转移酶调节海马和皮质神经元中神经元活动驱动的线粒体生物能学。我们显示神经元活性上调线粒体中的O-GlcNAcylation。线粒体O-GlcNAcylation由活性驱动的葡萄糖消耗促进，这允许神经元根据燃料的可用性来补偿高能量消耗。为了确定负责这些调整的蛋白质，我们绘制了神经元的线粒体O-GlcNAcome。最后,我们确定，当O-GlcNAcylation动力学被阻止时，神经元无法满足活动驱动的代谢需求。我们的发现表明，O-GlcNAcylation在神经元中提供了燃料依赖性前馈控制机制，以基于神经元活性优化线粒体性能。因此，该机制将神经元代谢与线粒体生物能学偶联，并在维持能量稳态中起关键作用。
