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Mitochondrial serine catabolism safeguards maintenance of the hematopoietic stem cell pool in homeostasis and injury
Cell Stem Cell ( IF 19.8 ) Pub Date : 2024-08-23 , DOI: 10.1016/j.stem.2024.07.009 Changhong Du 1 , Chaonan Liu 2 , Kuan Yu 1 , Shuzhen Zhang 1 , Zeyu Fu 1 , Xinliang Chen 1 , Weinian Liao 1 , Jun Chen 1 , Yimin Zhang 1 , Xinmiao Wang 3 , Mo Chen 1 , Fang Chen 1 , Mingqiang Shen 1 , Cheng Wang 1 , Shilei Chen 1 , Song Wang 1 , Junping Wang 1
Cell Stem Cell ( IF 19.8 ) Pub Date : 2024-08-23 , DOI: 10.1016/j.stem.2024.07.009 Changhong Du 1 , Chaonan Liu 2 , Kuan Yu 1 , Shuzhen Zhang 1 , Zeyu Fu 1 , Xinliang Chen 1 , Weinian Liao 1 , Jun Chen 1 , Yimin Zhang 1 , Xinmiao Wang 3 , Mo Chen 1 , Fang Chen 1 , Mingqiang Shen 1 , Cheng Wang 1 , Shilei Chen 1 , Song Wang 1 , Junping Wang 1
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Hematopoietic stem cells (HSCs) employ a very unique metabolic pattern to maintain themselves, while the spectrum of their metabolic adaptations remains incompletely understood. Here, we uncover a distinct and heterogeneous serine metabolism within HSCs and identify mouse HSCs as a serine auxotroph whose maintenance relies on exogenous serine and the ensuing mitochondrial serine catabolism driven by the hydroxymethyltransferase 2 (SHMT2)-methylene-tetrahydrofolate dehydrogenase 2 (MTHFD2) axis. Mitochondrial serine catabolism primarily feeds NAD(P)H generation to maintain redox balance and thereby diminishes ferroptosis susceptibility of HSCs. Dietary serine deficiency, or genetic or pharmacological inhibition of the SHMT2-MTHFD2 axis, increases ferroptosis susceptibility of HSCs, leading to impaired maintenance of the HSC pool. Moreover, exogenous serine protects HSCs from irradiation-induced myelosuppressive injury by fueling mitochondrial serine catabolism to mitigate ferroptosis. These findings reframe the canonical view of serine from a nonessential amino acid to an essential niche metabolite for HSC pool maintenance.
中文翻译：
线粒体丝氨酸分解代谢保障造血干细胞库的稳态和损伤的维持
造血干细胞（HSC）采用非常独特的代谢模式来维持自身，但其代谢适应范围仍不完全清楚。在这里，我们发现了 HSC 内独特且异质的丝氨酸代谢，并将小鼠 HSC 鉴定为丝氨酸营养缺陷型，其维持依赖于外源丝氨酸以及由羟甲基转移酶 2 (SHMT2)-亚甲基四氢叶酸脱氢酶 2 (MTHFD2) 轴驱动的线粒体丝氨酸分解代谢。 。线粒体丝氨酸分解代谢主要促进 NAD(P)H 的产生以维持氧化还原平衡，从而降低 HSC 铁死亡的易感性。膳食丝氨酸缺乏，或 SHMT2-MTHFD2 轴的遗传或药理学抑制，会增加 HSC 铁死亡的易感性，导致 HSC 池的维持受损。此外，外源丝氨酸通过促进线粒体丝氨酸分解代谢来减轻铁死亡，从而保护 HSC 免受辐射引起的骨髓抑制损伤。这些发现重新构建了丝氨酸的经典观点，从非必需氨基酸转变为维持 HSC 池的必需代谢物。
更新日期：2024-08-23
中文翻译：
线粒体丝氨酸分解代谢保障造血干细胞库的稳态和损伤的维持
造血干细胞（HSC）采用非常独特的代谢模式来维持自身，但其代谢适应范围仍不完全清楚。在这里，我们发现了 HSC 内独特且异质的丝氨酸代谢，并将小鼠 HSC 鉴定为丝氨酸营养缺陷型，其维持依赖于外源丝氨酸以及由羟甲基转移酶 2 (SHMT2)-亚甲基四氢叶酸脱氢酶 2 (MTHFD2) 轴驱动的线粒体丝氨酸分解代谢。 。线粒体丝氨酸分解代谢主要促进 NAD(P)H 的产生以维持氧化还原平衡，从而降低 HSC 铁死亡的易感性。膳食丝氨酸缺乏，或 SHMT2-MTHFD2 轴的遗传或药理学抑制，会增加 HSC 铁死亡的易感性，导致 HSC 池的维持受损。此外，外源丝氨酸通过促进线粒体丝氨酸分解代谢来减轻铁死亡，从而保护 HSC 免受辐射引起的骨髓抑制损伤。这些发现重新构建了丝氨酸的经典观点，从非必需氨基酸转变为维持 HSC 池的必需代谢物。
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