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  3. Mitochondrial serine catabolism safeguards maintenance of the hematopoietic stem cell pool in homeostasis and injury

Mitochondrial serine catabolism safeguards maintenance of the hematopoietic stem cell pool in homeostasis and injury

  • Cell Stem Cell. 2024 Oct 3;31(10):1484-1500.e9. doi: 10.1016/j.stem.2024.07.009.
Changhong Du 1,  Chaonan Liu 2,  Kuan Yu 3,  Shuzhen Zhang 3,  Zeyu Fu 3,  Xinliang Chen 3,  Weinian Liao 3,  Jun Chen 3,  Yimin Zhang 3,  Xinmiao Wang 4,  Mo Chen 3,  Fang Chen 3,  Mingqiang Shen 3,  Cheng Wang 3,  Shilei Chen 3,  Song Wang 5,  Junping Wang 6
Affiliations

Affiliations

  • 1 State Key Laboratory of Trauma and Chemical Poisoning, Institute of Combined Injury, Chongqing Engineering Research Center for Nanomedicine, College of Preventive Medicine, Army Medical University (Third Military Medical University), Chongqing 400038, China. Electronic address: changhongdu@tmmu.edu.cn.
  • 2 State Key Laboratory of Trauma and Chemical Poisoning, Institute of Combined Injury, Chongqing Engineering Research Center for Nanomedicine, College of Preventive Medicine, Army Medical University (Third Military Medical University), Chongqing 400038, China; Frontier Medical Training Brigade, Army Medical University (Third Military Medical University), Xinjiang 831200, China.
  • 3 State Key Laboratory of Trauma and Chemical Poisoning, Institute of Combined Injury, Chongqing Engineering Research Center for Nanomedicine, College of Preventive Medicine, Army Medical University (Third Military Medical University), Chongqing 400038, China.
  • 4 State Key Laboratory of Trauma and Chemical Poisoning, Institute of Combined Injury, Chongqing Engineering Research Center for Nanomedicine, College of Preventive Medicine, Army Medical University (Third Military Medical University), Chongqing 400038, China; Department of Hematology, The General Hospital of Western Theater Command, Chengdu, Sichuan 610008, China.
  • 5 State Key Laboratory of Trauma and Chemical Poisoning, Institute of Combined Injury, Chongqing Engineering Research Center for Nanomedicine, College of Preventive Medicine, Army Medical University (Third Military Medical University), Chongqing 400038, China. Electronic address: gunnm1981@163.com.
  • 6 State Key Laboratory of Trauma and Chemical Poisoning, Institute of Combined Injury, Chongqing Engineering Research Center for Nanomedicine, College of Preventive Medicine, Army Medical University (Third Military Medical University), Chongqing 400038, China. Electronic address: wangjunping@tmmu.edu.cn.
PMID: 39181130 DOI: 10.1016/j.stem.2024.07.009
Abstract

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.

Keywords

NADPH; SHMT2; ferroptosis; hematopoietic stem cell; heterogeneity; ionizing radiation; mitochondrial serine catabolism; myelosuppressive injury.

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