Mitochondrial Serine Catabolism Maintains Hematopoietic Stem Cell Pool in Homeostasis and Injury

Hematology Life Sciences Medicine Cell Biology Biochemistry
mitochondria serine metabolism hematopoietic stem cells ferroptosis homeostasis radiation injury

Research Background

The maintenance and repair of the hematopoietic system are crucial for the continuation of life and health in an organism. As the foundation of the hematopoietic system, the stability of hematopoietic stem cells (HSCs) is particularly important. The maintenance of the HSC pool relies on intrinsic and extrinsic factors, among which the hypoxic environment and antioxidant mechanisms play a significant role in HSC survival. With the deepening research in cellular metabolism, scientists have found that amino acid metabolism is also vital for maintaining HSC function, especially serine metabolism. However, because serine is traditionally considered a non-essential amino acid that many adult cells can synthesize themselves, its role in healthy adult cells has been less studied.

This paper, published in the journal “Cell Stem Cell” by scholars Changhong Du, Chaonan Liu, and others, conducts an in-depth study of the metabolic requirements of hematopoietic stem cells and the specific metabolic pathways of serine. They found that HSCs are highly dependent on exogenous serine to produce NAD(P)H to maintain intracellular redox balance, thereby avoiding cellular ferroptosis. Furthermore, the study also points out the protective role of exogenous serine in radiation damage to HSCs, providing new insights and potential clinical application value for the maintenance of HSCs.

Research Process

Characteristic Analysis of Serine Metabolism

The research team conducted single-cell RNA sequencing (scRNA-seq) to analyze the gene expression related to serine metabolism in mouse and human HSCs, revealing the characteristic serine metabolism of HSCs. The experimental results show that HSCs exhibit significant serine dependency (serine nutritional deficiency), with low expression of serine synthesis enzymes (PHGDH) and high expression of serine transport proteins and metabolic enzymes, indicating that HSCs are more reliant on exogenous serine rather than self-synthesis. Furthermore, through cell marker analysis, the study further confirmed the significant activity of mitochondrial serine metabolism in HSCs.

Necessity of Exogenous Serine for HSC Maintenance

To test the role of exogenous serine, the research team placed mice in a serine/glycine deficient dietary environment. The results showed that HSCs in such a deficient environment exhibited a significant reduction in cell yield, along with leukopenia and anemia. In in vivo and in vitro experiments, researchers found that the growth of HSCs was significantly impaired in the absence of exogenous serine, demonstrating the importance of exogenous serine for maintaining the HSC pool.

Role of Mitochondrial Serine Metabolism in HSCs

The research team focused on analyzing the role of serine hydroxymethyltransferase 2 (SHMT2) in HSCs, finding that mitochondrial SHMT2 generates 1C units and NAD(P)H through serine metabolism to maintain redox balance and anti-ferroptosis ability. In SHMT2 gene knockout mouse models, HSCs exhibited significant ferroptotic susceptibility and obstacles in maintaining the HSC pool, further proving the crucial role of mitochondrial serine metabolism.

Relationship Between Serine Metabolism and Ferroptotic Susceptibility

To explore the molecular basis of ferroptosis in HSCs, the research team conducted transcriptome analysis and found that HSCs with serine metabolism defects exhibited higher ferroptotic susceptibility and significantly elevated lipid peroxidation levels. When treated with the ferroptosis inhibitor Liproxstatin-1 (Lip-1), the maintenance and ferroptotic susceptibility of HSCs were significantly improved, further verifying the impact of mitochondrial serine metabolism on ferroptosis.

Protective Role of Exogenous Serine Against Radiation Damage

Through in vivo experiments, the study found that exogenous serine had a protective effect against radiation-induced bone marrow suppressive damage. In radiation damage mouse models, supplementation with serine significantly elevated NAD(P)H levels and reduced ferroptotic susceptibility in HSCs, thereby improving the maintenance of HSCs and the survival rate of mice. This finding provides a new direction for the protection against radiation damage.

Research Results

This study reveals the uniqueness of mitochondrial serine metabolism in HSCs and its key role in maintaining redox balance. Specifically, HSCs depend on exogenous serine to produce NAD(P)H through the SHMT2-MTHFD2 axis, inhibiting the occurrence of cellular ferroptosis to maintain the stability of the HSC pool. Serine deficiency or SHMT2 gene knockout leads to increased ferroptotic susceptibility in HSCs, further resulting in hematopoietic disorders.

Moreover, by promoting mitochondrial serine metabolism, exogenous serine provides protection to HSCs during radiation damage. This result reveals the unique metabolic demand of HSCs for serine from a metabolic perspective, offering new insights for treating bone marrow suppressive damage.

Research Conclusions and Significance

This research redefines the role of serine in the biology of HSCs, repositioning it from a “non-essential amino acid” to a “key metabolite” crucial for maintaining the HSC pool. The study reveals that HSCs maintain redox balance and prevent ferroptosis through the mitochondrial serine metabolism driven by the SHMT2-MTHFD2 axis, ensuring the long-term stability of HSCs. Additionally, the study demonstrates the protective role of exogenous serine in radiation damage, which has important implications for the clinical treatment of radiation injury.

In terms of practical applications, the research points out the potential clinical value of serine in HSC maintenance, suggesting that monitoring and supplementing exogenous serine can help mitigate bone marrow suppressive damage. Furthermore, the study suggests serine metabolism as a potential target for tumor treatment, particularly targeting cancers related to radioresistance and chemoresistance.

Research Highlights

  1. Revealed the serine nutritional deficiency characteristics of HSCs: The particularity of HSCs in serine metabolism primarily relies on exogenous serine and the mitochondrial serine metabolic pathway.
  2. Elucidated the key role of the SHMT2-MTHFD2 axis: This metabolic axis maintains redox balance by generating NAD(P)H, thereby inhibiting ferroptosis in HSCs.
  3. Provided new insights into radiation damage protection: The protective effect of exogenous serine in radiation damage offers new ideas for treating bone marrow suppressive damage.
  4. Potential value of serine metabolism in tumor therapy: The potential of serine metabolism as a metabolic target may provide new directions for tumor treatment.

Other Valuable Information

The study employed a plethora of mouse models in its experimental design, including serine-deficient and SHMT2 gene knockout models, utilizing various biological and molecular biological techniques to comprehensively analyze serine metabolism. In addition, the study employed various in vitro agents (such as the ferroptosis inhibitor Lip-1, antioxidant NAC, etc.) to validate the critical role of serine metabolism, providing valuable data support and methodological guidance for subsequent biomedical research.

This research significantly expands the understanding of the metabolic needs of HSCs, revealing the key role of serine metabolism in HSC maintenance and radiation damage, providing new directions for future treatments of hematological diseases. Future research can further explore the diversity of serine metabolism in HSCs and adaptive mechanisms in different pathological environments, offering more possibilities for the diagnosis and treatment of diseases related to hematopoietic stem cells.