1 research outputs found
Sensitivity of hematopoietic stem cells to mitochondrial dysfunction by SdhD gene deletion
It is established that hematopoietic stem cells (HSC) in the hypoxic bone marrow have adapted their metabolism to oxygen-limiting
conditions. This adaptation includes suppression of mitochondrial activity, induction of anerobic glycolysis, and activation of
hypoxia-inducible transcription factor 1α (Hif1α)-dependent gene expression. During progression of hematopoiesis, a metabolic
switch towards mitochondrial oxidative phosphorylation is observed, making this organelle essential for determining cell fate
choice in bone marrow. However, given that HSC metabolism is essentially oxygen-independent, it is still unclear whether
functional mitochondria are absolutely required for their survival. To assess the actual dependency of these undifferentiated cells
on mitochondrial function, we have performed an analysis of the hematopoiesis in a mouse mutant, named SDHD-ESR, with
inducible deletion of the mitochondrial protein-encoding SdhD gene. This gene encodes one of the subunits of the mitochondrial
complex II (MCII). In this study, we demonstrate that, in contrast to what has been previously established, survival of HSC, and also
myeloid and B-lymphoid progenitors, depends on proper mitochondrial activity. In addition, gene expression analysis of these
hematopoietic lineages in SDHD-ESR mutants calls into question the proposed activation of Hif1α in response to MCII dysfunction.Ministerio de Ciencia e Innovación SAF2009-06970Junta de Andalucía CTS-4589Instituto de Salud Carlos III PI-0355-201