PKM2 is a key factor to regulate neurogenesis and cognition by controlling lactate homeostasis

Pengyan He; Bingjun Zhang; Wei Jiang; Fan Zhu; Ziqi Liang; Lin Gao; Yuhong Zhang; Yuge Wang; Caixia Wu; Changyong Tang

doi:10.1016/j.stemcr.2024.11.011

PKM2 is a key factor to regulate neurogenesis and cognition by controlling lactate homeostasis

Stem Cell Reports. 2024 Dec 12:102381. doi: 10.1016/j.stemcr.2024.11.011. Online ahead of print.

Authors

Pengyan He¹, Bingjun Zhang¹, Wei Jiang¹, Fan Zhu¹, Ziqi Liang², Lin Gao², Yuhong Zhang³, Yuge Wang⁴, Caixia Wu⁵, Changyong Tang⁶

Affiliations

¹ Department of Neurology, The Third Affiliated Hospital of Sun Yat-Sen University, 600 Tianhe Road, Guangzhou 510630, Guangdong Province, China.
² State Key Laboratory for Molecular and Developmental Biology, Institute of Genetics and Developmental Biology, Chinese Academy of Sciences, Beijing 100101, China.
³ The Affiliated Brain Hospital, Guangzhou Medical University, Key Laboratory of Neurogenetics and Channelopathies of Guangdong Province and the Ministry of Education of China, Guangzhou Medical University, Guangzhou 510370, China.
⁴ Department of Neurology, The Third Affiliated Hospital of Sun Yat-Sen University, 600 Tianhe Road, Guangzhou 510630, Guangdong Province, China. Electronic address: wangyuge@mail.sysu.edu.cn.
⁵ Institute of Biological and Medical Engineering, Guangdong Academy of Sciences, Guangzhou 510632, China; National Engineering Research Center for Healthcare Devices, Institute of Biological and Medical Engineering, Guangdong Academy of Sciences, Guangzhou 510316, China; Guangdong Provincial Key Laboratory of Medical Electronic Instruments and Polymer Material Products, Institute of Biological and Medical Engineering, Guangdong Academy of Sciences, Guangzhou 510316, China. Electronic address: caixia52@163.com.
⁶ Department of Neurology, The Third Affiliated Hospital of Sun Yat-Sen University, 600 Tianhe Road, Guangzhou 510630, Guangdong Province, China; Guangdong Provincial Key Laboratory of Diabetology, The Third Affiliated Hospital of Sun Yat-sen University, Guangzhou, Guangdong 510630, China. Electronic address: tangchy23@mail.sysu.edu.cn.

PMID: 39706177
DOI: 10.1016/j.stemcr.2024.11.011

Abstract

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.

Keywords: PKM2; cognitive function; lactate homeostasis; neural stem cells.