Journal article
Iron control of erythroid development by a novel aconitase-associated regulatory pathway
Blood, Vol.116(1), pp.97-108
Red Cells, Iron, and Erythropoiesis
07/08/2010
DOI: 10.1182/blood-2009-10-251496
PMCID: PMC2904585
PMID: 20407036
Abstract
Human red cell differentiation requires the action of erythropoietin on committed progenitor cells. In iron deficiency, committed erythroid progenitors lose responsiveness to erythropoietin, resulting in hypoplastic anemia. To address the basis for iron regulation of erythropoiesis, we established primary hematopoietic cultures with transferrin saturation levels that restricted erythropoiesis but permitted granulopoiesis and megakaryopoiesis. Experiments in this system identified as a critical regulatory element the aconitases, multifunctional iron-sulfur cluster proteins that metabolize citrate to isocitrate. Iron restriction suppressed mitochondrial and cytosolic aconitase activity in erythroid but not granulocytic or megakaryocytic progenitors. An active site aconitase inhibitor, fluorocitrate, blocked erythroid differentiation in a manner similar to iron deprivation. Exogenous isocitrate abrogated the erythroid iron restriction response in vitro and reversed anemia progression in iron-deprived mice. The mechanism for aconitase regulation of erythropoiesis most probably involves both production of metabolic intermediates and modulation of erythropoietin signaling. One relevant signaling pathway appeared to involve protein kinase Cα/β, or possibly protein kinase Cδ, whose activities were regulated by iron, isocitrate, and erythropoietin.
Details
- Title: Subtitle
- Iron control of erythroid development by a novel aconitase-associated regulatory pathway
- Creators
- Grant C. Bullock - University of VirginiaLorrie L. Delehanty - University of VirginiaAnne-Laure Talbot - University of VirginiaSara L. Gonias - University of VirginiaWing-Hang Tong - Molecular Medicine Program, National Institute of Child Health and Human Development, Bethesda, MDTracey A. Rouault - Molecular Medicine Program, National Institute of Child Health and Human Development, Bethesda, MDBrian Dewar - University of North Carolina at Chapel HillJeffrey M. Macdonald - University of North Carolina at Chapel HillJason J. Chruma - University of VirginiaAdam N. Goldfarb - University of Virginia
- Resource Type
- Journal article
- Publication Details
- Blood, Vol.116(1), pp.97-108
- Publisher
- American Society of Hematology
- Series
- Red Cells, Iron, and Erythropoiesis
- DOI
- 10.1182/blood-2009-10-251496
- PMID
- 20407036
- PMCID
- PMC2904585
- ISSN
- 0006-4971
- eISSN
- 1528-0020
- Grant note
- F32 HL0860046 / National Institutes of Health
- Language
- English
- Date published
- 07/08/2010
- Academic Unit
- Pathology
- Record Identifier
- 9984697640102771
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