The mitochondrial respiratory chain is essential for haematopoietic stem cell function

Elena Ansó; Samuel E. Weinberg; Lauren P. Diebold; Benjamin J. Thompson; Sébastien Malinge; Paul T. Schumacker; Xin Liu; Yuannyu Zhang; Zhen Shao; Mya Steadman; Kelly M. Marsh; Jian Xu; John D. Crispino; Navdeep S. Chandel

doi:10.1038/ncb3529

The mitochondrial respiratory chain is essential for haematopoietic stem cell function

Elena Ansó, Samuel E. Weinberg, Lauren P. Diebold, Benjamin J. Thompson, Sébastien Malinge, Paul T. Schumacker, Xin Liu, Yuannyu Zhang, Zhen Shao, Mya Steadman, Kelly M. Marsh, Jian Xu, John D. Crispino, Navdeep S. Chandel^*

^*Corresponding author for this work

Research output: Contribution to journal › Article › peer-review

239 Scopus citations

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)
Pages (from-to)	614-625
Number of pages	12
Journal	Nature Cell Biology
Volume	19
Issue number	6
DOIs	https://doi.org/10.1038/ncb3529
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

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This output contributes to the following UN Sustainable Development Goals (SDGs)

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title = "The mitochondrial respiratory chain is essential for haematopoietic stem cell function",

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.",

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AU - Schumacker, Paul T.

AU - Liu, Xin

AU - Zhang, Yuannyu

AU - Shao, Zhen

AU - Steadman, Mya

AU - Marsh, Kelly M.

AU - Xu, Jian

AU - Crispino, John D.

AU - Chandel, Navdeep S.

PY - 2017/5/31

Y1 - 2017/5/31

N2 - 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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The mitochondrial respiratory chain is essential for haematopoietic stem cell function

Abstract

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ASJC Scopus subject areas

UN SDGs

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