Department of Pharmacology, School of Medicine, Nanjing University of Chinese Medicine, Nanjing, China.
Jiangsu Key Laboratory of Neurodegeneration, Department of Pharmacology, Nanjing Medical University, Nanjing, China.
Nat Neurosci. 2023 Dec;26(12):2081-2089. doi: 10.1038/s41593-023-01476-4. Epub 2023 Nov 23.
It is generally thought that under basal conditions, neurons produce ATP mainly through mitochondrial oxidative phosphorylation (OXPHOS), and glycolytic activity only predominates when neurons are activated and need to meet higher energy demands. However, it remains unknown whether there are differences in glucose metabolism between neuronal somata and axon terminals. Here, we demonstrated that neuronal somata perform higher levels of aerobic glycolysis and lower levels of OXPHOS than terminals, both during basal and activated states. We found that the glycolytic enzyme pyruvate kinase 2 (PKM2) is localized predominantly in the somata rather than in the terminals. Deletion of Pkm2 in mice results in a switch from aerobic glycolysis to OXPHOS in neuronal somata, leading to oxidative damage and progressive loss of dopaminergic neurons. Our findings update the conventional view that neurons uniformly use OXPHOS under basal conditions and highlight the important role of somatic aerobic glycolysis in maintaining antioxidant capacity.
一般认为，在基础状态下，神经元主要通过线粒体氧化磷酸化（OXPHOS）产生 ATP，而当神经元被激活并需要满足更高的能量需求时，糖酵解活性才会占主导地位。然而，神经元胞体和轴突末梢之间的葡萄糖代谢是否存在差异仍不清楚。在这里，我们证明了在基础状态和激活状态下，神经元胞体的有氧糖酵解水平高于轴突末梢，而 OXPHOS 水平则低于轴突末梢。我们发现，糖酵解酶丙酮酸激酶 2（PKM2）主要定位于胞体而不是末梢。在小鼠中删除 Pkm2 会导致神经元胞体从有氧糖酵解向 OXPHOS 的转变，从而导致氧化损伤和多巴胺能神经元的进行性丧失。我们的发现更新了神经元在基础条件下普遍使用 OXPHOS 的传统观点，并强调了胞体有氧糖酵解在维持抗氧化能力方面的重要作用。
