Hematopoietic stem cells (HSCs) adapt their metabolism to maintenance and proliferation; however, the mechanism remains incompletely understood. Here, we demonstrated that homeostatic HSCs exhibited high amino acid (AA) catabolism to reduce cellular AA levels, which activated the GCN2-eIF2α axis, a protein synthesis inhibitory checkpoint to restrain protein synthesis for maintenance. Furthermore, upon proliferation conditions, HSCs enhanced mitochondrial oxidative phosphorylation (OXPHOS) for higher energy production but decreased AA catabolism to accumulate cellular AAs, which inactivated the GCN2-eIF2α axis to increase protein synthesis and coupled with proteotoxic stress. Importantly, GCN2 deletion impaired HSC function in repopulation and regeneration. Mechanistically, GCN2 maintained proteostasis and inhibited Src-mediated AKT activation to repress mitochondrial OXPHOS in HSCs. Moreover, the glycolytic metabolite, NAD⁺ precursor nicotinamide riboside (NR), accelerated AA catabolism to activate GCN2 and sustain the long-term function of HSCs. Overall, our study uncovered direct links between metabolic alterations and translation control in HSCs during homeostasis and proliferation.

造血干细胞 (HSC) 使其代谢适应维持和增殖；但是，该机制仍未完全了解。在这里，我们证明了稳态 HSC 表现出高氨基酸 (AA) 分解代谢以降低细胞 AA 水平，从而激活 GCN2-eIF2α 轴，这是一种蛋白质合成抑制检查点，可抑制蛋白质合成以维持维持。此外，在增殖条件下，HSCs 增强线粒体氧化磷酸化 (OXPHOS) 以产生更高的能量，但降低 AA 分解代谢以积累细胞 AA，从而使 GCN2-eIF2α 轴失活以增加蛋白质合成并与蛋白毒性应激相结合。重要的是，GCN2 缺失会损害 HSC 在再增殖和再生中的功能。机械地，GCN2 维持蛋白质稳态并抑制 Src 介导的 AKT 活化以抑制 HSC 中的线粒体 OXPHOS。此外，糖酵解代谢物 NAD⁺前体烟酰胺核苷 (NR)，加速 AA 分解代谢以激活 GCN2 并维持 HSC 的长期功能。总体而言，我们的研究揭示了 HSC 在稳态和增殖过程中的代谢改变和翻译控制之间的直接联系。