title: 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.
authors.affiliation: Instituto de Biomedicina de Sevilla (IBiS), Hospital Universitario Virgen del Rocío, CSIC, Universidad de Sevilla, Seville, Spain.
authors.forename: José Antonio
authors.initials: JA
authors.lastname: Bejarano-García
authors.affiliation: Instituto de Biomedicina de Sevilla (IBiS), Hospital Universitario Virgen del Rocío, CSIC, Universidad de Sevilla, Seville, Spain.
authors.forename: África
authors.initials: Á
authors.lastname: Millán-Uclés
authors.affiliation: Instituto de Biomedicina de Sevilla (IBiS), Hospital Universitario Virgen del Rocío, CSIC, Universidad de Sevilla, Seville, Spain.
authors.forename: Iván V
authors.initials: IV
authors.lastname: Rosado
authors.affiliation: Instituto de Biomedicina de Sevilla (IBiS), Hospital Universitario Virgen del Rocío, CSIC, Universidad de Sevilla, Seville, Spain.
authors.forename: Luís Ignacio
authors.initials: LI
authors.lastname: Sánchez-Abarca
authors.affiliation: Instituto de Biomedicina de Sevilla (IBiS), Hospital Universitario Virgen del Rocío, CSIC, Universidad de Sevilla, Seville, Spain.|Departamento de Hematología, Hospital Universitario Virgen del Rocío, Seville, Spain.
authors.forename: Teresa
authors.initials: T
authors.lastname: Caballero-Velázquez
authors.affiliation: Instituto de Biomedicina de Sevilla (IBiS), Hospital Universitario Virgen del Rocío, CSIC, Universidad de Sevilla, Seville, Spain.
authors.forename: María José
authors.initials: MJ
authors.lastname: Durán-Galván
authors.affiliation: Instituto de Biomedicina de Sevilla (IBiS), Hospital Universitario Virgen del Rocío, CSIC, Universidad de Sevilla, Seville, Spain.|Departamento de Hematología, Hospital Universitario Virgen del Rocío, Seville, Spain.
authors.forename: José Antonio
authors.initials: JA
authors.lastname: Pérez-Simón
authors.affiliation: Instituto de Biomedicina de Sevilla (IBiS), Hospital Universitario Virgen del Rocío, CSIC, Universidad de Sevilla, Seville, Spain.|Departamento de Hematología, Hospital Universitario Virgen del Rocío, Seville, Spain.
authors.forename: José I
authors.initials: JI
authors.lastname: Piruat
mesh_terms: D000818:Animals; D001402:B-Lymphocytes / Q000276:immunology; D001853:Bone Marrow / Q000378:metabolism; D015687:Cell Hypoxia; D019070:Cell Lineage; D002470:Cell Survival; D003114:Colony-Forming Units Assay; D042963:Electron Transport Complex II / Q000378:metabolism*; D017353:Gene Deletion; D005786:Gene Expression Regulation; D006412:Hematopoietic Stem Cells / Q000378:metabolism*; D007962:Leukocytes / Q000378:metabolism; D008565:Membrane Proteins / Q000378:metabolism*; D051379:Mice; D008928:Mitochondria / Q000378:metabolism*; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D013154:Spleen / Q000166:cytology; D013385:Succinate Dehydrogenase; D013601:T-Lymphocytes / Q000276:immunology; D013950:Thymus Gland / Q000473:pathology
chemical_list: D008565:Membrane Proteins; D012333:RNA, Messenger; D042963:Electron Transport Complex II; C574938:SDHD protein, mouse; D013385:Succinate Dehydrogenase