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

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2016-12-08

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Bejarano-García, José Antonio
Millán-Uclés, África
Rosado, Iván V
Sánchez-Abarca, Luís Ignacio
Caballero-Velázquez, Teresa
Durán-Galván, María José
Pérez-Simón, José Antonio
Piruat, José I

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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.

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Animals
B-Lymphocytes
Bone Marrow
Cell Hypoxia
Cell Lineage
Cell Survival
Colony-Forming Units Assay
Electron Transport Complex II
Gene Deletion
Gene Expression Regulation
Hematopoietic Stem Cells
Leukocytes
Membrane Proteins
Mice
Mitochondria
RNA, Messenger
Spleen
Succinate Dehydrogenase
T-Lymphocytes
Thymus Gland

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