Sensitivity of hematopoietic stem cells to mitochondrial dysfunction by SdhD gene deletion

Abstract

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.

Dye-Independent Methods Reveal Elevated Mitochondrial Mass in Hematopoietic Stem Cells

“…We showed previously that the mitochondrial fusion protein, Mitofusin 2 (Mfn2), is required for the maintenance of HSCs with extensive lymphoid potential, and that this effect was mediated through enhanced buffering of intracellular calcium by mitochondria (Luchsinger et al, 2016). Though recent publications do indicate an important role for respiration in HSC maintenance as well (Anso et al, 2017; Bejarano-Garcia et al, 2016; Guitart et al, 2017), these findings suggest that mitochondria perform specific and essential roles in HSCs, including but likely not limited to calcium buffering, that may not be directly dependent on ATP production. We therefore suggest that the role of mitochondria in the biology of HSCs may need to be revisited.…”

“…In contrast to most mature cells, HSCs rely predominantly on glycolytic ATP production (Ito and Suda, 2014; Shyh-Chang et al, 2013; Simsek et al, 2010; Takubo et al, 2013). While shown to be important for HSC maintenance (Anso et al, 2017; Bejarano-Garcia et al, 2016; Guitart et al, 2017), some experimental data suggest that mitochondrial respiration may indeed be more dispensable for HSCs than for progenitors (Norddahl et al, 2011; Yu et al, 2013). Consistent with their reduced mitochondrial respiration, HSCs have been reported to be endowed with low mitochondrial mass based on staining with mitochondrial dyes (Mantel et al, 2012; Mohrin et al, 2015; Romero-Moya et al, 2013; Simsek et al, 2010; Takubo et al, 2013; Vannini et al, 2016; Xiao et al, 2012).…”

Reactive oxygen species in haematopoiesis: leukaemic cells take a walk on the wild side

“…Although HSCs exhibit low mitochondrial metabolism, recent work suggests the importance of mitochondrial function for their survival [ 87 ] and self-renewal [ 88 ]. Mitochondrial biogenesis is activated as HSCs differentiate [ 89 ].…”

Phosphate Transporter Profiles in Murine and Human Thymi Identify Thymocytes at Distinct Stages of Differentiation

“…While thymocyte differentiation has not been evaluated in these mice, the high level of PiT2 in immature thymocytes progressing through the β-selection checkpoint suggests that thymocyte differentiation would be negatively affected, as detected in mice with a conditional deletion of GLUT1 (37). In support of a potential role for PiT2 in early thymus differentiation, deletion of genes that alter thymocyte metabolism, such as apoptosis-inducing factor (AIF) (114) and SdhD (115), have resulted in a block in thymocyte differentiation, at the DN3/DN4 transition. Finally, it will be of interest to determine whether patients with PFBC exhibit decreased thymocyte differentiation, evaluated as a function of TRECs, especially given the association in several genetic immunodeficiencies with CNS involvement (116).…”