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 journalArticlepeer-review

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

ASJC Scopus subject areas

  • Cell Biology

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