Université Paris-Saclay, CEA, CNRS, MIRCen, Laboratoire des Maladies Neurodégénératives, Fontenay-aux-Roses, France.
Institute of Functional Biology and Genomics (IBFG), Universidad de Salamanca, CSIC, Salamanca, Spain; Centro de Investigación Biomédica en Red sobre Fragilidad y Envejecimiento Saludable (CIBERFES), Institute of Biomedical Research of Salamanca, 37007, Salamanca, Spain.
Prog Neurobiol. 2021 Feb;197:101896. doi: 10.1016/j.pneurobio.2020.101896. Epub 2020 Aug 14.
Brain energy metabolism is often considered as a succession of biochemical steps that metabolize the fuel (glucose and oxygen) for the unique purpose of providing sufficient ATP to maintain the huge information processing power of the brain. However, a significant fraction (10-15 %) of glucose is shunted away from the ATP-producing pathway (oxidative phosphorylation) and may be used to support other functions. Recent studies have pointed to the marked compartmentation of energy metabolic pathways between neurons and glial cells. Here, we focused our attention on the biosynthesis of l-serine, a non-essential amino acid that is formed exclusively in glial cells (mostly astrocytes) by re-routing the metabolic fate of the glycolytic intermediate, 3-phosphoglycerate (3PG). This metabolic pathway is called the phosphorylated pathway and transforms 3PG into l-serine via three enzymatic reactions. We first compiled the available data on the mechanisms that regulate the flux through this metabolic pathway. We then reviewed the current evidence that is beginning to unravel the roles of l-serine both in the healthy and diseased brain, leading to the notion that this specific metabolic pathway connects glial metabolism with synaptic activity and plasticity. We finally suggest that restoring astrocyte-mediated l-serine homeostasis may provide new therapeutic strategies for brain disorders.
脑能量代谢通常被认为是一系列生化步骤，其代谢燃料（葡萄糖和氧气）是为了提供足够的 ATP 来维持大脑巨大的信息处理能力这一独特目的。然而，相当一部分（10-15%）的葡萄糖会偏离产生 ATP 的途径（氧化磷酸化），可能用于支持其他功能。最近的研究表明，神经元和神经胶质细胞之间的能量代谢途径存在明显的分隔。在这里，我们将注意力集中在 l-丝氨酸的生物合成上，l-丝氨酸是一种非必需氨基酸，仅在神经胶质细胞（主要是星形胶质细胞）中通过重排糖酵解中间产物 3-磷酸甘油酸（3PG）的代谢命运而形成。这种代谢途径称为磷酸化途径，通过三个酶促反应将 3PG 转化为 l-丝氨酸。我们首先汇编了有关调节该代谢途径通量的机制的现有数据。然后，我们回顾了当前的证据，这些证据开始揭示 l-丝氨酸在健康和患病大脑中的作用，从而提出了这样一种观点，即这种特定的代谢途径将神经胶质细胞代谢与突触活动和可塑性联系起来。最后，我们建议恢复星形胶质细胞介导的 l-丝氨酸动态平衡可能为脑部疾病提供新的治疗策略。
