Journal
BLOOD
Volume 116, Issue 1, Pages 97-108Publisher
AMER SOC HEMATOLOGY
DOI: 10.1182/blood-2009-10-251496
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Funding
- Ruth L. Kirschstein National Research Service
- National Institutes of Health [F32 HL0860046]
- University of Virginia
- University of Virginia Cancer Center
- NCI Cancer Center [P30 CA44579]
- Ivy Foundation
- National Institute of Diabetes and Digestive and Kidney Diseases [R01 DK079924]
- Roche Foundation for Anemia Research
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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 C alpha/beta, or possibly protein kinase C delta, whose activities were regulated by iron, isocitrate, and erythropoietin. (Blood. 2010; 116(1): 97-108)
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