The mitochondrial respiratory chain is essential for haematopoietic stem cell function

Nature Cell Biology
Elena AnsóNavdeep S Chandel

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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Datasets Mentioned

BETA
GSE95341
PXD006054

Methods Mentioned

BETA
RNA-seq
histone acetylation
Flow Cytometry
Assay
Biosample

Software Mentioned

FlowJo
Skyline
Graphpad Prism
[UNK]
Cufflinks
TopHat
Xcalibur

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