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Blood, 15 May 2006, Vol. 107, No. 10, pp. 4159-4167.
Prepublished online as a Blood First Edition Paper on January 19, 2006; DOI 10.1182/blood-2005-05-1809.
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RED CELLS
Remodeling the regulation of iron metabolism during erythroid differentiation to ensure efficient heme biosynthesis
Matthias Schranzhofer,
Manfred Schifrer,
Javier Antonio Cabrera,
Stephan Kopp,
Peter Chiba,
Hartmut Beug, and
Ernst W. Müllner
From the Department of Medical Biochemistry, Division of Molecular Biology, Max F. Perutz Laboratories, University Departments at the Vienna Biocenter, Medical University of Vienna; Institute of Medical Chemistry, Medical University of Vienna; and Institute of Molecular Pathology (IMP), Vienna, Austria.
Terminal erythropoiesis is accompanied by extreme demand for iron to ensure proper hemoglobinization. Thus, erythroblasts must modify the "standard" post-transcriptional feedback regulation, balancing expression of ferritin (Fer; iron storage) versus transferrin receptor (TfR1; iron uptake) via specific mRNA binding of iron regulatory proteins (IRPs). Although erythroid differentiation involves high levels of incoming iron, TfR1 mRNA stability must be sustained and Fer mRNA translation must not be activated because iron storage would counteract hemoglobinization. Furthermore, translation of the erythroid-specific form of aminolevulinic acid synthase (ALAS-E) mRNA, catalyzing the first step of heme biosynthesis and regulated similarly as Fer mRNA by IRPs, must be ensured. We addressed these questions using mass cultures of primary murine erythroid progenitors from fetal liver, either undergoing sustained proliferation or highly synchronous differentiation. We indeed observed strong inhibition of Fer mRNA translation and efficient ALAS-E mRNA translation in differentiating erythroblasts. Moreover, in contrast to self-renewing cells, TfR1 stability and IRP mRNA binding were no longer modulated by iron supply. These and additional data stemming from inhibition of heme synthesis with succinylacetone or from iron overload suggest that highly efficient utilization of iron in mitochondrial heme synthesis during normal erythropoiesis alters the regulation of iron metabolism via the IRE/IRP system.
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