Journal article
Manganese superoxide dismutase depletion in murine hematopoietic stem cells perturbs iron homeostasis, globin switching, and epigenetic control in erythrocyte precursor cells
Free radical biology & medicine, Vol.56, pp.17-27
03/2013
DOI: 10.1016/j.freeradbiomed.2012.11.018
PMCID: PMC3578015
PMID: 23219873
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 byproducts 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 anti-oxidant enzyme that governs steady-state levels of the superoxide in the mitochondrial matrix. Using hematopoietic stem cell-specific conditional
Sod2
knock-out 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 of histone post-translational modifications, a likely cause of at least some of the aberrant gene expression noted. From a therapeutic translational perspective, mitochondrially-targeted superoxide-scavenging anti-oxidants 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.
Details
- Title: Subtitle
- Manganese superoxide dismutase depletion in murine hematopoietic stem cells perturbs iron homeostasis, globin switching, and epigenetic control in erythrocyte precursor cells
- Creators
- Adam J Case - Free Radical and Radiation Biology Program, Department of Radiation Oncology, Holden Comprehensive Cancer Center, The University of Iowa, Iowa City, IA 52242, USAJoshua M Madsen - Free Radical and Radiation Biology Program, Department of Radiation Oncology, Holden Comprehensive Cancer Center, The University of Iowa, Iowa City, IA 52242, USADavid G Motto - Division of Hematology Oncology, Department of Internal Medicine, The University of Iowa, Iowa City, IA 52242, USADavid K Meyerholz - Department of Pathology, The University of Iowa, Iowa City, IA 52242, USAFrederick E Domann - Free Radical and Radiation Biology Program, Department of Radiation Oncology, Holden Comprehensive Cancer Center, The University of Iowa, Iowa City, IA 52242, USA
- Resource Type
- Journal article
- Publication Details
- Free radical biology & medicine, Vol.56, pp.17-27
- DOI
- 10.1016/j.freeradbiomed.2012.11.018
- PMID
- 23219873
- PMCID
- PMC3578015
- NLM abbreviation
- Free Radic Biol Med
- ISSN
- 0891-5849
- eISSN
- 1873-4596
- Grant note
- R01 CA115438 || CA / National Cancer Institute : NCI P01 HL091842 || HL / National Heart, Lung, and Blood Institute : NHLBI
- Language
- English
- Date published
- 03/2013
- Academic Unit
- Pathology; Surgery; Radiation Oncology
- Record Identifier
- 9984047675302771
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