Abstract
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.
Original language | English (US) |
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Pages (from-to) | 614-625 |
Number of pages | 12 |
Journal | Nature Cell Biology |
Volume | 19 |
Issue number | 6 |
DOIs | |
State | Published - May 31 2017 |
Funding
This work was supported by the NIH (R35CA197532) to N.S.C., NIH (T32 GM008061) to L.P.D., NIH (T32 T32HL076139) to S.E.W. J.X. is supported by the NIH/NIDDK grants K01DK093543 and R01DK111430 and the Cancer Prevention and Research Institute of Texas (CPRIT) New Investigator award (RR140025). We thank Robert H. Lurie Cancer Center Flow Cytometry facility supported by NCI CCSG P30 CA060553 for their invaluable assistance. Proteomics services were performed by the Northwestern Proteomics Core Facility, generously supported by NCI CCSG P30 CA060553 awarded to the Robert H. Lurie Comprehensive Cancer Center and the National Resource for Translational and Developmental Proteomics supported by P41 GM108569.
ASJC Scopus subject areas
- Cell Biology