He Pengyan, Zhang Bingjun, Jiang Wei, Zhu Fan, Liang Ziqi, Gao Lin, Zhang Yuhong, Wang Yuge, Wu Caixia, Tang Changyong
Department of Neurology, The Third Affiliated Hospital of Sun Yat-Sen University, 600 Tianhe Road, Guangzhou 510630, Guangdong Province, China.
State Key Laboratory for Molecular and Developmental Biology, Institute of Genetics and Developmental Biology, Chinese Academy of Sciences, Beijing 100101, China.
Stem Cell Reports. 2025 Jan 14;20(1):102381. doi: 10.1016/j.stemcr.2024.11.011. Epub 2024 Dec 19.
Adult hippocampal neurogenesis (AHN), the process of generating new neurons from adult neural stem/progenitor cells (NSPCs), is crucial for cognitive functions and is influenced by numerous factors, including metabolic processes. Pyruvate kinase M2 (PKM2), a key rate-limiting enzyme in glycolysis, catalyzes the production of pyruvate, which undergoes either oxidative phosphorylation or anaerobic oxidation. We observed that PKM2 is highly expressed in NSPCs, but its significance remains unclear for AHN and cognition. Using knockdown or knockout strategies, we discovered that PKM2 deficiency led to reduced AHN and impaired cognitive functions. Furthermore, we observed that knockout of PKM2 resulted in lower L-lactate levels, and supplementing L-lactate in PKM2 knockout mice improved AHN and cognitive functions. Mechanistically, L-lactate restored neurogenesis via monocarboxylate transporter 2 (MCT2), but not hydroxycarboxylic acid receptor 1. In summary, our findings demonstrate that PKM2 is essential for AHN, and lactate supplementation can restore neurogenesis in an MCT2-dependent manner.
成体海马神经发生（AHN）是指从成体神经干细胞/祖细胞（NSPCs）产生新神经元的过程，对认知功能至关重要，并且受包括代谢过程在内的多种因素影响。丙酮酸激酶M2（PKM2）是糖酵解中的关键限速酶，催化丙酮酸的生成，丙酮酸可进行氧化磷酸化或无氧氧化。我们观察到PKM2在NSPCs中高表达，但其对AHN和认知的意义仍不清楚。使用敲低或敲除策略，我们发现PKM2缺陷导致AHN减少和认知功能受损。此外，我们观察到敲除PKM2会导致L-乳酸水平降低，而在PKM2敲除小鼠中补充L-乳酸可改善AHN和认知功能。从机制上讲，L-乳酸通过单羧酸转运体2（MCT2）恢复神经发生，但不是通过羟基羧酸受体1。总之，我们的研究结果表明PKM2对AHN至关重要，补充乳酸可以以MCT2依赖的方式恢复神经发生。
