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

Research output: Contribution to journalArticle

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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 languageEnglish (US)
Pages (from-to)614-625
Number of pages12
JournalNature Cell Biology
Volume19
Issue number6
DOIs
StatePublished - May 31 2017

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Electron Transport
Hematopoietic Stem Cells
Fetal Stem Cells
Respiration
Adult Stem Cells
NAD
Histone Demethylases
Maintenance
Pancytopenia
Electron Transport Complex III
DNA Methylation
Histones
Anemia
Cell Differentiation
Cell Proliferation
Phenotype
Rieske iron-sulfur protein
DNA

ASJC Scopus subject areas

  • Cell Biology

Cite this

Ansó, E., Weinberg, S. E., Diebold, L. P., Thompson, B. J., Malinge, S., Schumacker, P. T., ... Chandel, N. S. (2017). The mitochondrial respiratory chain is essential for haematopoietic stem cell function. Nature Cell Biology, 19(6), 614-625. https://doi.org/10.1038/ncb3529

The mitochondrial respiratory chain is essential for haematopoietic stem cell function. / Ansó, Elena; Weinberg, Samuel E.; Diebold, Lauren P.; Thompson, Benjamin J.; Malinge, Sébastien; Schumacker, Paul T.; Liu, Xin; Zhang, Yuannyu; Shao, Zhen; Steadman, Mya; Marsh, Kelly M.; Xu, Jian; Crispino, John D.; Chandel, Navdeep S.

In: Nature Cell Biology, Vol. 19, No. 6, 31.05.2017, p. 614-625.

Research output: Contribution to journalArticle

Ansó, E, Weinberg, SE, Diebold, LP, Thompson, BJ, Malinge, S, Schumacker, PT, Liu, X, Zhang, Y, Shao, Z, Steadman, M, Marsh, KM, Xu, J, Crispino, JD & Chandel, NS 2017, 'The mitochondrial respiratory chain is essential for haematopoietic stem cell function', Nature Cell Biology, vol. 19, no. 6, pp. 614-625. https://doi.org/10.1038/ncb3529
Ansó E, Weinberg SE, Diebold LP, Thompson BJ, Malinge S, Schumacker PT et al. The mitochondrial respiratory chain is essential for haematopoietic stem cell function. Nature Cell Biology. 2017 May 31;19(6):614-625. https://doi.org/10.1038/ncb3529
Ansó, Elena ; Weinberg, Samuel E. ; Diebold, Lauren P. ; Thompson, Benjamin J. ; Malinge, Sébastien ; Schumacker, Paul T. ; Liu, Xin ; Zhang, Yuannyu ; Shao, Zhen ; Steadman, Mya ; Marsh, Kelly M. ; Xu, Jian ; Crispino, John D. ; Chandel, Navdeep S. / The mitochondrial respiratory chain is essential for haematopoietic stem cell function. In: Nature Cell Biology. 2017 ; Vol. 19, No. 6. pp. 614-625.
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