The mitochondrial respiratory chain is essential for haematopoietic stem cell function

Area of Science:

• Cell Biology
• Hematology
• Mitochondrial Biology

Background:

• Adult and fetal hematopoietic stem cells (HSCs) primarily use glycolysis for stemness.
• The role of mitochondrial respiration in HSC function remains unclear.

Purpose of the Study:

• To investigate the necessity of mitochondrial respiration for HSC function.
• To determine the impact of impaired respiration on fetal and adult HSCs.

Main Methods:

• Utilized mouse models with genetic inactivation of the mitochondrial complex III subunit Rieske iron-sulfur protein (RISP).
• Analyzed HSC proliferation, differentiation, respiration, NAD+/NADH ratios, DNA/histone methylation, and 2-hydroxyglutarate (2HG) levels.

Main Results:

• RISP deficiency in fetal HSCs impaired respiration, decreased NAD+/NADH ratio, and inhibited differentiation, causing anemia and prenatal death.
• RISP-null fetal HSCs showed increased DNA and histone methylation due to elevated 2HG.
• RISP inactivation in adult HSCs led to loss of quiescence, pancytopenia, and lethality.

Conclusions:

• Mitochondrial respiration is dispensable for HSC proliferation but essential for fetal HSC differentiation.
• Respiration is critical for maintaining adult HSC quiescence and overall HSC function.