Presenting Author:

Lauren Diebold, B.S.

Principal Investigator:

Navdeep Chandel, Ph.D.

Department:

Medicine

Keywords:

Hematopoietic stem cells (HSCs), mitochondrial respiration, 2-hydroxyglutarate (2-HG), epigenetics.

Location:

Third Floor, Feinberg Pavilion, Northwestern Memorial Hospital

B73 - Basic Science

Respiration is essential for hematopoietic stem cell function

Adult and fetal hematopoietic 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), encoded by the Uqcrfs1 gene, in fetal mouse HSCs results in anemia and prenatal death. RISP null fetal HSCs, displayed impaired respiration, resulting in a decreased NAD+/NADH ratio and an increase in glycolysis. While they were viable and able to robustly proliferate in vivo, RISP null fetal HSCs had impaired differentiation, resulting in a depletion of the progenitor pool. RNA seq analysis revealed widespread changes in gene expression due to loss of RISP in fetal HSCs. Furthermore, RISP null fetal HSCs and progenitors exhibited an increase in both DNA and histone methylation concomitant with increases in 2-hydroxyglutarate (2-HG), a metabolite known to inhibit DNA and histone demethylases. RISP inactivation in adult HSCs also impaired respiration, resulting in a decreased NAD+/NADH ratio, increased glycolysis and loss of quiescence, followed by rapid bone marrow depletion resulting in severe pancytopenia and lethality. The effect of RISP ablation in fetal or adult HSCs was cell-autonomous. Together, these data indicate that respiration is dispensable for adult or fetal HSC proliferation, but essential for fetal HSC differentiation and maintenance of adult HSC quiescence.