The mitochondrial respiratory chain is essential for haematopoietic stem cell function

Nat Cell Biol. 2017 Jun;19(6):614-625. doi: 10.1038/ncb3529. Epub 2017 May 15.


Adult and fetal haematopoietic stem cells (HSCs) display a glycolytic phenotype, which is required for maintenance of stemness; however, whether mitochondrial respiration is required to maintain HSC function is not known. Here we report that loss of the mitochondrial complex III subunit Rieske iron-sulfur protein (RISP) in fetal mouse HSCs allows them to proliferate but impairs their differentiation, resulting in anaemia and prenatal death. RISP-null fetal HSCs displayed impaired respiration resulting in a decreased NAD+/NADH ratio. RISP-null fetal HSCs and progenitors exhibited an increase in both DNA and histone methylation associated with increases in 2-hydroxyglutarate (2HG), a metabolite known to inhibit DNA and histone demethylases. RISP inactivation in adult HSCs also impaired respiration resulting in loss of quiescence concomitant with severe pancytopenia and lethality. Thus, respiration is dispensable for adult or fetal HSC proliferation, but essential for fetal HSC differentiation and maintenance of adult HSC quiescence.

Publication types

  • Comparative Study

MeSH terms

  • Adult Stem Cells / metabolism*
  • Adult Stem Cells / pathology
  • Anemia / blood
  • Anemia / genetics
  • Animals
  • Cell Death
  • Cell Proliferation*
  • Cells, Cultured
  • Cellular Senescence
  • Electron Transport
  • Electron Transport Complex III / deficiency
  • Electron Transport Complex III / genetics
  • Electron Transport Complex III / metabolism*
  • Energy Metabolism*
  • Epigenesis, Genetic
  • Female
  • Fetal Stem Cells / metabolism*
  • Fetal Stem Cells / pathology
  • Genotype
  • Glutarates / metabolism
  • Hematopoiesis*
  • Hematopoietic Stem Cells / metabolism*
  • Hematopoietic Stem Cells / pathology
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Mitochondria / metabolism*
  • Mitochondria / pathology
  • NAD / metabolism
  • Phenotype
  • Pregnancy
  • Signal Transduction
  • Time Factors


  • Glutarates
  • Rieske iron-sulfur protein
  • NAD
  • alpha-hydroxyglutarate
  • Electron Transport Complex III