title: Iron control of erythroid development by a novel aconitase-associated regulatory pathway.
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 Calpha/beta, or possibly protein kinase Cdelta, whose activities were regulated by iron, isocitrate, and erythropoietin.
authors.affiliation: Department of Pathology, University of Virginia School of Medicine, Charlottesville, VA 22908, USA.
authors.forename: Grant C
authors.initials: GC
authors.lastname: Bullock
authors.forename: Lorrie L
authors.initials: LL
authors.lastname: Delehanty
authors.forename: Anne-Laure
authors.initials: AL
authors.lastname: Talbot
authors.forename: Sara L
authors.initials: SL
authors.lastname: Gonias
authors.forename: Wing-Hang
authors.initials: WH
authors.lastname: Tong
authors.forename: Tracey A
authors.initials: TA
authors.lastname: Rouault
authors.forename: Brian
authors.initials: B
authors.lastname: Dewar
authors.forename: Jeffrey M
authors.initials: JM
authors.lastname: Macdonald
authors.forename: Jason J
authors.initials: JJ
authors.lastname: Chruma
authors.forename: Adam N
authors.initials: AN
authors.lastname: Goldfarb
mesh_terms: D018798:Anemia, Iron-Deficiency / Q000097:blood / Q000209:etiology / Q000378:metabolism; D000818:Animals; D002454:Cell Differentiation / Q000187:drug effects; D002478:Cells, Cultured; D015672:Erythroid Precursor Cells / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D004920:Erythropoiesis / Q000187:drug effects*; D005260:Female; D005434:Flow Cytometry; D006801:Humans; D015151:Immunoblotting; D007501:Iron / Q000494:pharmacology*; D000090463:Iron Deficiencies; D035941:Iron Regulatory Protein 1 / Q000235:genetics / Q000378:metabolism*; D007523:Isocitrates / Q000008:administration & dosage; D020014:K562 Cells; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D034622:RNA Interference; D015398:Signal Transduction / Q000187:drug effects
chemical_list: D007523:Isocitrates; C034219:isocitric acid; D007501:Iron; D035941:Iron Regulatory Protein 1
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