The major traffic of iron in the body is to the erythroid marrow (Fig. 1). Each day, almost 200 billion RBCs are produced in a normal adult to replace a similar number reaching the end of their lifespan, amounting to about 24 mL of packed RBC/day containing about 24 mg of iron. Erythroid precursors and most other iron-utilizing cells require iron complexed by transferrin. Apotransferrin, a form of transferrin not carrying iron, is a single-chain glycoprotein with two structurally similar lobes. The binding of a ferric (Fe3+) ion to one of these lobes yields monoferric transferrin; binding of ions to both yields diferric transferrin. The transferrin saturation is the proportion of the available iron-binding sites on transferrin that are occupied by iron atoms, expressed as a percentage. In humans, almost all circulating plasma apotransferrin is synthesized by hepatocytes. Apotransferrin is not lost in delivering iron but is reused repeatedly as the half-life of the protein is about 8 days. After delivering iron to cells, apotransferrin is promptly returned to the plasma to function again as an iron transporter, completing 100 to 200 cycles of iron delivery during its lifetime in the circulation.

Fig1. ACQUISITION AND USE OF IRON BY ERYTHROID PRECURSORS. Iron is imported in the transferrin (Tf) cycle and principally used for the synthesis of heme. See text for details. ABC7, Adenosine triphosphate−binding cassette, subfamily B (MDR/TAP), member 7; DMT1, divalent metal transporter 1; Fe2 Tf, diferric transferrin; FLVCR, feline leukemia virus subgroup C cellular receptor; Hb, hemoglobin; IRP1, iron-regulatory protein 1; STEAP3, six-transmembrane epithelial antigen of the prostate 3; TfR1, transferrin receptor 1. (Modified with permission from Beaumont C, Delaby C. Recycling iron in normal and pathological states. Semin Hematol. 2009;46:328.)

Transferrin receptors on the cell surface bind monoferric or diferric transferrin. Two different forms of the transferrin receptor exist, encoded by two separate genes. Transferrin receptor 1 is ubiquitously expressed and functions as the physiologic transferrin iron importer on all iron-requiring cells. Transferrin receptor 2 is expressed in hepatocytes, functioning in the control of iron supply by regulating hepcidin expression, and in erythroid precursors,4 coordinating erythropoiesis with iron availability. Transferrin receptor 1 is a transmembrane glycoprotein dimer composed of two identical subunits linked by a disulfide bond. Each transferrin receptor 1 can bind two molecules of transferrin; if each transferrin is diferric, the dimeric receptor can carry a total of four atoms of transferrin-bound iron. The affinity of transferrin receptor 1 for transferrin depends both on the iron content of transferrin and on the pH. Transferrin receptor 1 has a low affinity for apotransferrin; an intermediate affinity for monoferric transferrin; and the highest affinity for diferric transferrin, estimated at 2 × 10⁻⁹ to 7 × 10⁻⁹ M. Under physiologic conditions, the affinity of transferrin receptor 1 for diferric transferrin is more than fourfold greater than that for monoferric transferrin. At a pH of about 5 in the endosome, the affinity of transferrin receptor 1 for apotransferrin increases to that of diferric transferrin.

Iron delivery to an erythroid cell (see Fig. 1) begins with the binding of one or two molecules of monoferric or diferric transferrin to transferrin receptor 1.4 The efficiency of iron delivery to the cell depends on the amounts of monoferric and diferric plasma transferrin available, with the iron distributed between the two forms according to the principles of chemical equilibrium, which also govern the interaction of the two forms with transferrin receptor 1. During nor mal erythropoiesis and a normal transferrin saturation of about 33%, most of the iron supply to cells is derived from diferric transferrin, providing four atoms of iron with each cycle. At a transferrin saturation of about 19%, equal amounts of iron are provided by mono ferric and diferric transferrin; at lower saturations, most of the iron is derived from the monoferric form. Whether monoferric or diferric, the fate of transferrin bound to the transferrin receptor is the same. When bound, the iron-bearing transferrin−receptor complex rapidly clusters with other transferrin−receptor complexes in a clathrin-coated pit that is promptly internalized. Within the cytoplasm, the coated vesicle is rapidly stripped of clathrin, and the uncoated vesicles fuse to become multivesicular endosomes. A proton pump then acidifies the endosome internal pH to less than 6. In the acidic environment of the endosome, both transferrin and transferrin receptor 1 undergo conformational changes that cause iron release. The released ferric iron is reduced by the ferrireductase six-transmembrane epithelial antigen of the prostate 3 (STEAP3) to the ferrous form and then transported across the endosomal membrane through DMT1 (SLC11A2). Low pH in the endosome increases the affinity of the now iron-free apotransferrin for the transferrin receptor so that the complex remains intact as it is transported back to the cell surface within the endosome. On exposure to the neutral pH of the plasma, the apotransferrin loses its affinity for the transferrin receptor and is released from the membrane, making both the apotransferrin and the transferrin receptor 1 available for reuse (see Fig. 1).

Most of the iron transported across the endosomal membrane through DMT1 is then directed to the mitochondria for use in the synthesis of heme and iron-sulfur clusters (see Fig. 1) with the rest destined for cytoplasmic proteins that coordinate iron through their amino acid side chains and for cytoplasmic ferritin that stores an inorganic iron complex in the cavity of a shell-like structure.

Iron can be imported from the cytosol across the mitochondrial membrane by the transmembrane protein mitoferrin 1 (MFRN1; SLC25A37). Transport of iron from endosomes into mitochondria for heme synthesis by direct contact between the organelles (“kiss and run”), avoiding the cytosol, also has been proposed. Heme (ferrous protoporphyrin IX), a planar molecule consisting of an atom of ferrous iron in the center of a tetrapyrrole ring, is then synthesized in eight biochemical reactions, with the first and final three reactions catalyzed by mitochondrial enzymes and the four intermediate reactions taking place in the cytoplasm. Most heme is then bound to α- or β-globin subunits that combine to form α–β dimers that in turn join to form the functional α2-β2-tetramer of hemoglobin (see Fig. 1). Small amounts of heme are incorporated into heme enzymes and cytochromes. Iron is also used for another class of pros thetic groups, iron-sulfur clusters, assembled within mitochondria and in the cytosol (see Fig. 1). The cytosolic iron chaperones poly(rC)-binding proteins 1 and 2 (PCBP1, PCBP2) may ferry sur plus iron to multiple intracellular destinations: cytosolic ferritin for storage, to some cytosolic nonheme enzymes, and in specialized cell types for export into plasma to meet the iron needs of the organism.17 Transferrin receptor 2 (TfR2), which binds iron-loaded transferrin with an affinity some 25-fold less than that of transferrin receptor 1, functions as a sensor of iron bound to transferrin and is not involved in cellular iron uptake. In erythroid precursors, transferrin receptor 2 coordinates erythropoiesis with iron availability, a vital mechanism for adaptation to iron deficiency. Transferrin receptor 2, a component of the erythropoietin receptor complex, stabilizes the receptor on the cell surface and modulates the sensitivity of the developing erythroid cells to erythropoietin. By simultaneously sensing the concentration of iron-loaded transferrin in developing erythroid cells and in hepatocytes (see later), transferrin receptor 2 permits erythropoiesis to adapt to the level of the iron supply while modulating iron absorption and the release of iron from stores to meet the erythropoietic (and organismal) requirement for iron. Erythroid precursors have multiple other mechanisms to coordinate their iron usage with systemic iron availability, to conserve iron, and to share excess iron with the rest of the organism. These mechanisms likely evolved to avoid the adverse consequences of the erythropoietic system using more than its share of iron at the expense of the rest of the organism.

• Reduction of responsiveness to erythropoietin: Iron regulation of erythroid differentiation helps match the rate of erythropoiesis to iron supply. With iron deficiency, an TfR2-dependent pathway also reduces the responsiveness of erythroid progenitors to erythropoietin. During iron deficiency, decreased erythroid use for RBC production helps preserve the supply of iron for vital functions in other tissues.

 • Inhibition of erythroid heme synthesis: Heme synthesis is coordinated with iron availability through an iron-regulatory element in the 5′-untranslated region of the mRNA for eALAS, the erythroid-specific initial enzyme in the heme synthetic pathway. If intracellular iron availability is low, binding of an iron-regulatory protein will inhibit heme synthesis by preventing translation of the mRNA.

• Inhibition of globin and other protein translation: If the lack of iron leads to heme deficiency, the heme-regulated translational inhibitor (HRI) is activated and, acting through the α-subunit of eukaryotic initiation factor 2, slows most protein synthesis to coordinate the translation of globin mRNAs with the intracellular heme concentration. This action of the HRI is responsible for the physiologic adaptation that produces hypochromic, microcytic erythrocytes in iron deficiency. More recent data indicate that mTorc1 (mechanistic target of rapamycin complex 1), the master regulator of cell growth in proportion to available nutrients, coordinates with HRI to regulate the synthesis of cellular macromolecules and thereby determines the size of erythrocytes.

• Export of iron through ferroportin: Developing erythroblasts synthesize ferroportin to export iron. Their expression of ferroportin is regulated principally by hepcidin, providing another means to coordinate erythroid iron use with systemic iron availability. In erythroid precursors (and in duodenal enterocyte), two ferroportin transcripts are present: the ubiquitously expressed fer roportin (FPN1A), with an iron-responsive element in its 5′ un translated region, and FPN1B, which lacks the iron-responsive element. During erythroid cell differentiation, FPN1B is therefore not subject to translational repression by the iron-regulatory pro tein system, thereby permitting the export of iron from erythroid precursor cells during the critical period when cells commit to proliferation and differentiation, express high levels of transferrin receptor 1, and rapidly accumulate iron. As a consequence, erythropoiesis may be partially suppressed when nonerythropoietic tis sues are at risk for iron deficiency. Iron export from erythroblasts via FPN1B may account for the development of iron deficiency anemia as an initial, early manifestation of systemic iron deficiency. Nonetheless, when the cells begin to produce hemoglobin, FPN1B expression diminishes and FPN1A predominates, allowing erythroid cells to limit iron export through the iron-responsive element iron-regulatory protein system and to efficiently manufacture heme.

• Export of excess heme: Erythroblasts have the capacity to export excess heme through the feline leukemia virus subgroup C cellular receptor and avoid heme toxicity.

 • Storage of excess iron: Cytosolic ferritin can be synthesized and utilized to deposit surplus iron in a safe form from which iron can be recovered when needed. Also, a mitochondrial ferritin, consisting of homopolymers of a nuclear gene-encoded H-type ferritin, can be expressed to protect against mitochondrial iron accumulation in sideroblastic anemia and some other disorders.

 • Recovery of the nonfunctional iron content during terminal differentiation: Orthochromatic erythroblasts, with nuclei that are unable to synthesize DNA, gradually lose most mitochondria and halt RNA synthesis but continue to produce hemoglobin. The pyknotic nucleus is finally extruded through the erythroblast membrane with the loss of about 5% to 10% of the hemoglobin that had been synthesized previously, with the extruded material recycled by erythroblastic island macrophages. The resultant reticulocyte continues to synthesize hemoglobin for another 2 to 3 days until the cellular supply of mRNA is exhausted, producing as much as 30% of the total hemoglobin complement of the RBC. Eventually, the reticulocyte is released from the marrow, remodeled, and pitted of siderotic granules and debris within the spleen, and these excess materials are recycled by splenic macrophages.

اخر الاخبار

اخبار العتبة العباسية المقدسة

30 قارئًا يشاركون بـ18 ختمة قرآنية رمضانية في محافظة الديوانية

الحوزة العلمية تقيم مجلس فاتحة الشهيد السيد علي الخامنئي (رضوان الله عليه)

تأهّل 5 مشاركين للمرحلة النهائية من جائزة العميد الدولية لتلاوة القرآن الكريم

محفل نهج البلاغة الأسبوعي في ذي قار يشهد تقديم المحاضرة الخامسة

المزيد

الآخبار الصحية

مركب طبيعي في القهوة يحمينا من التهابات اللثة

داء السكري لا يرفع السكر فقط.. بل يزيد خطر الإصابة بأمراض القلب!

اكتشاف سبب غير متوقع لضعف الذاكرة والتركيز

نصائح علمية لتقوية دماغك وتقليل التدهور العقلي

المزيد

الآخبار التكنلوجية

باحثون يرصدون أثر تغيّر المناخ في دم البشر

الجميع يحلم.. لماذا يتذكر البعض أحلامهم بينما ينسى آخرون؟

حرق الأمونيا.. كيف يساعد محطات الكهرباء في اليابان على إزالة الكربون؟

الشمس تقذف نتوءا عملاقا باتجاه قطبها الشمالي

المزيد

مواضيع ذات صلة

Recycling of Erythrocyte Iron by Macrophages

Essential Features OF Red Blood Cell Homeostasis

sentinel lymph node biopsy (SLNB, Lymphoscintigraphy)

salivary gland nuclear imaging (Parotid gland nuclear imaging)

pulmonary angiography (Pulmonary arteriography)

Fever of Unknown Origin

Biological Markers of Mental Illness

New Biomarkers of Bone Remodeling : Sclerostin

New Biomarkers of Bone Remodeling : RANK-RANKL-OPG

Splenic Abscesses

Liver Abscesses

Intraperitoneal Abscesses