title: Manganese superoxide dismutase depletion in murine hematopoietic stem cells perturbs iron homeostasis, globin switching, and epigenetic control in erythrocyte precursor cells.
abstract: Heme synthesis partially occurs in the mitochondrial matrix; thus there is a high probability that enzymes and intermediates important in the production of heme will be exposed to metabolic by-products including reactive oxygen species. In addition, the need for ferrous iron for heme production, Fe/S coordination, and other processes occurring in the mitochondrial matrix suggests that aberrant fluxes of reactive oxygen species in this compartment might perturb normal iron homeostasis. Manganese superoxide dismutase (Sod2) is an antioxidant enzyme that governs steady-state levels of the superoxide in the mitochondrial matrix. Using hematopoietic stem cell-specific conditional Sod2 knockout mice we observed increased superoxide concentrations in red cell progeny, which caused significant pathologies including impaired erythrocytes and decreased ferrochelatase activity. Animals lacking Sod2 expression in erythroid precursors also displayed extramedullary hematopoiesis and systemic iron redistribution. Additionally, the increase in superoxide flux in erythroid precursors caused abnormal gene regulation of hematopoietic transcription factors, globins, and iron-response genes. Moreover, the erythroid precursors also displayed evidence of global changes in histone posttranslational modifications, a likely cause of at least some of the aberrant gene expression noted. From a therapeutic translational perspective, mitochondrially targeted superoxide-scavenging antioxidants partially rescued the observed phenotype. Taken together, our findings illuminate the superoxide sensitivity of normal iron homeostasis in erythrocyte precursors and suggest a probable link between mitochondrial redox metabolism and epigenetic control of nuclear gene regulation during mammalian erythropoiesis.
authors.affiliation: Free Radical and Radiation Biology Program, Department of Radiation Oncology, Holden Comprehensive Cancer Center, Iowa City, IA 52242, USA.
authors.forename: Adam J
authors.initials: AJ
authors.lastname: Case
authors.forename: Joshua M
authors.initials: JM
authors.lastname: Madsen
authors.forename: David G
authors.initials: DG
authors.lastname: Motto
authors.forename: David K
authors.initials: DK
authors.lastname: Meyerholz
authors.forename: Frederick E
authors.initials: FE
authors.lastname: Domann
mesh_terms: D000818:Animals; D044127:Epigenesis, Genetic; D017353:Gene Deletion; D005914:Globins / Q000378:metabolism*; D006412:Hematopoietic Stem Cells / Q000201:enzymology / Q000378:metabolism*; D006706:Homeostasis; D007501:Iron / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D013482:Superoxide Dismutase / Q000172:deficiency* / Q000235:genetics / Q000378:metabolism
chemical_list: D005914:Globins; D007501:Iron; D013482:Superoxide Dismutase