Journal
NATURE CELL BIOLOGY
Volume 19, Issue 6, Pages 614-+Publisher
NATURE PUBLISHING GROUP
DOI: 10.1038/ncb3529
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Funding
- NIH [R35CA197532, T32 GM008061, T32 T32HL076139]
- NIH/NIDDK [K01DK093543, R01DK111430]
- Cancer Prevention and Research Institute of Texas (CPRIT) [RR140025]
- NCI [CCSG P30 CA060553]
- [P41 GM108569]
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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.
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