L‐arginine homeostasis governs adult neural stem cell activation by modulating energy metabolism in vivo. (6th February 2023)

• Record Type: Journal Article
• Authors: Xu, Mingyue; Guo, Ye; Wang, Min; Luo, Xing; Shen, Xuning; Li, Zhimin; Wang, Lei; Guo, Weixiang
• Is Part Of: EMBO journal. Volume 42:Number 6(2023)
• Page Start: n/a
• Page End: n/a
• Publication Date: 2023-02-06
• Subjects: Adult neurogenesis -- Arginase‐II -- Hexokinase -- L‐arginine -- NSC pool; Molecular biology -- Periodicals; 572.805
• DOI: 10.15252/embj.2022112647
• Languages: English
• ISSNs: 0261-4189

Abstract

Abstract: Neurogenesis in the developing and adult brain is intimately linked to remodeling of cellular metabolism. However, it is still unclear how distinct metabolic programs and energy sources govern neural stem cell (NSC) behavior and subsequent neuronal differentiation. Here, we found that adult mice lacking the mitochondrial urea metabolism enzyme, Arginase‐II (Arg‐II), exhibited NSC overactivation, thereby leading to accelerated NSC pool depletion and decreased hippocampal neurogenesis over time. Mechanistically, Arg‐II deficiency resulted in elevated L‐arginine levels and induction of a metabolic shift from glycolysis to oxidative phosphorylation (OXPHOS) caused by impaired attachment of hexokinase‐I to mitochondria. Notably, selective inhibition of OXPHOS ameliorated NSC overactivation and restored abnormal neurogenesis in Arg‐II deficient mice. Therefore, Arg‐II‐mediated intracellular L‐arginine homeostasis directly influences the metabolic fitness of neural stem cells that is essential to maintain neurogenesis with age. Synopsis: The metabolic programs controlling neural stem cell (NSC) behavior and differentiation remain poorly defined. This study reports arginase‐II (Arg‐II)‐mediated breakdown of intracellular arginine as a nexus for maintenance of the NSC pool and neurogenesis in the adult mouse brain. Arg‐II deficiency increases L‐arginine levels in vivo, resulting in NSC overactivation and accelerated NSC depletion . NSC‐specific Arg‐II loss decreases adult neurogenesis. Elevated intracellular L‐arginine induce a metabolic shift from glycolysis to OXPHOS by inhibiting attachment of hexokinase‐1 to VDAC at mitochondria. Selective inhibition of OXPHOS restores NSC overactivation and aberrant adult neurogenesis in Arg‐II‐deficient mice. Abstract : Limiting intracellular L‐arginine defines metabolic pathway usage in neural stem cells and safeguards neurogenesis in the adult mouse brain.