Li Zhimin, Liang Ziqi, Qi Huan, Luo Xing, Wang Min, Du Zhuo, Guo Weixiang
State Key Laboratory for Molecular and Developmental Biology, Institute of Genetics and Developmental Biology, Chinese Academy of Sciences, Beijing 100101, China; University of Chinese Academy of Sciences, Beijing 100093, China.
State Key Laboratory for Molecular and Developmental Biology, Institute of Genetics and Developmental Biology, Chinese Academy of Sciences, Beijing 100101, China.
Dev Cell. 2025 Apr 21;60(8):1182-1198.e8. doi: 10.1016/j.devcel.2024.12.021. Epub 2025 Jan 6.
Lactate has emerged as a central metabolic fuel and an important signaling molecule. Its availability participates in various brain functions. Although lactate homeostasis is vital for adult hippocampal neurogenesis and cognition, it is still unknown how shuttles lactate across the plasma membrane of neural stem cells (NSCs) to control their activity and neurogenic potential. In this study, we show that monocarboxylate transporter (MCT)1 and MCT2, respectively, control efflux and influx of lactate in the murine NSCs, thereby maintaining intracellular lactate homeostasis. Mechanistically, lactate shuttling links histone lactylation to govern NSC proliferation through MDM2-p53 signaling pathway. Notably, genetic ablation of MCT2 from NSCs or pharmacological inhibition of MDM2-P53 interaction prevents voluntary running-induced NSC proliferation in the murine adult hippocampus. Taken together, our findings demonstrate that lactate shuttling controls histone lactylation, which acts as a nexus for controlling adult hippocampal neurogenesis.
乳酸已成为一种核心代谢燃料和重要的信号分子。其可用性参与多种脑功能。尽管乳酸稳态对成体海马神经发生和认知至关重要，但尚不清楚乳酸如何穿过神经干细胞（NSC）的质膜来控制其活性和神经发生潜能。在本研究中，我们表明单羧酸转运体（MCT）1和MCT2分别控制小鼠NSC中乳酸的外排和内流，从而维持细胞内乳酸稳态。从机制上讲，乳酸穿梭将组蛋白乳酸化与通过MDM2-p53信号通路调控NSC增殖联系起来。值得注意的是，从NSC中基因敲除MCT2或药理学抑制MDM2-P53相互作用可阻止小鼠成年海马中自愿运动诱导的NSC增殖。综上所述，我们的研究结果表明乳酸穿梭控制组蛋白乳酸化，而组蛋白乳酸化是控制成体海马神经发生的关键环节。
