Remodeling the regulation of iron metabolism during erythroid differentiation to ensure efficient heme biosynthesis

Abstract

Terminal erythropoiesis is accompanied by extreme demand for iron to ensure proper hemoglobinization. Thus, erythroblasts must modify the "standard" posttranscriptional 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. (Blood. 2006;107: 4159-4167)

Intraspecific variation in expression of candidate genes for osmoregulation, heme biosynthesis and stress resistance suggests local adaptation in European flounder (Platichthys flesus)

“…The ALAS gene was differently expressed between flounder populations in both gill and liver tissues and ALAS has previously been shown to be highly important for the iron/heme biosynthesis (Astner et al, 2005) primarily catalyzing the first step of heme biosynthesis (Schranzhofer et al, 2006). The observation of constitutive intraspecific variation in expression of ALAS across several tissues underlines the functional importance of the observed variation.…”

Direct interorganellar transfer of iron from endosome to mitochondrion

“…In addition, Martinez-Medellin and Schulman 27 observed that, when rabbit reticulocytes were treated with 59 Fe-Tf, radioiron was apparent only in either hemoglobin or a stromal-bound fraction. Furthermore, the recent study by Schranzhofer et al 49 showed a decrease in the sensitivity of the cytosolic iron regulatory proteins to Tf-derived iron in erythroid progenitors, as the cells differentiate. Together, these results are consistent with our model of iron delivery in Hb-synthesizing cells whereby the metal does not enter the cytosol, but is rapidly shuttled from endosome to the site of heme synthesis.…”

Human iron regulatory protein 2 is easily cleaved in its specific domain: consequences for the haem binding properties of the protein

“…For instance, IRPs play a prominent role in adjusting protoporphyrin synthesis to transferrin-bound iron availability in erythroblasts, as suggested by the zebrafish anaemia induced by sustained activation of IRP1 [3]. But synthesis of proteins participating in iron homoeostasis does not always fit with the IRE-IRP model of regulation along differentiation of the lineage [4,5]. Other regulatory events, including transcriptional ones, may combine with, or supersede, the translational control carried out by IRP.…”