Cellular iron metabolism
1999; Elsevier BV; Volume: 55; Linguagem: Inglês
10.1046/j.1523-1755.1999.055suppl.69002.x
ISSN1523-1755
Autores Tópico(s)Trace Elements in Health
ResumoCellular iron metabolism. Iron is essential for oxidation-reduction catalysis and bioenergetics, but unless appropriately shielded, iron plays a key role in the formation of toxic oxygen radicals that can attack all biological molecules. Hence, specialized molecules for the acquisition, transport (transferrin), and storage (ferritin) of iron in a soluble nontoxic form have evolved. Delivery of iron to most cells, probably including those of the kidney, occurs following the binding of transferrin to transferrin receptors on the cell membrane. The transferrin-receptor complexes are then internalized by endocytosis, and iron is released from transferrin by a process involving endosomal acidification. Cellular iron storage and uptake are coordinately regulated post-transcriptionally by cytoplasmic factors, iron-regulatory proteins 1 and 2 (IRP-1 and IRP-2). Under conditions of limited iron supply, IRP binding to iron-responsive elements (present in 5′ untranslated region of ferritin mRNA and 3′ untranslated region of transferrin receptor mRNA) blocks ferritin mRNA translation and stabilizes transferrin receptor mRNA. The opposite scenario develops when iron in the transit pool is plentiful. Moreover, IRP activities/levels can be affected by various forms of "oxidative stress" and nitric oxide. The kidney also requires iron for metabolic processes, and it is likely that iron deficiency or excess can cause disturbed function of kidney cells. Transferrin receptors are not evenly distributed throughout the kidney, and there is a cortical-to-medullary gradient in heme biosynthesis, with greatest activity in the cortex and least in the medulla. This suggests that there are unique iron/heme metabolism features in some kidney cells, but the specific aspects of iron and heme metabolism in the kidney are yet to be explained. Cellular iron metabolism. Iron is essential for oxidation-reduction catalysis and bioenergetics, but unless appropriately shielded, iron plays a key role in the formation of toxic oxygen radicals that can attack all biological molecules. Hence, specialized molecules for the acquisition, transport (transferrin), and storage (ferritin) of iron in a soluble nontoxic form have evolved. Delivery of iron to most cells, probably including those of the kidney, occurs following the binding of transferrin to transferrin receptors on the cell membrane. The transferrin-receptor complexes are then internalized by endocytosis, and iron is released from transferrin by a process involving endosomal acidification. Cellular iron storage and uptake are coordinately regulated post-transcriptionally by cytoplasmic factors, iron-regulatory proteins 1 and 2 (IRP-1 and IRP-2). Under conditions of limited iron supply, IRP binding to iron-responsive elements (present in 5′ untranslated region of ferritin mRNA and 3′ untranslated region of transferrin receptor mRNA) blocks ferritin mRNA translation and stabilizes transferrin receptor mRNA. The opposite scenario develops when iron in the transit pool is plentiful. Moreover, IRP activities/levels can be affected by various forms of "oxidative stress" and nitric oxide. The kidney also requires iron for metabolic processes, and it is likely that iron deficiency or excess can cause disturbed function of kidney cells. Transferrin receptors are not evenly distributed throughout the kidney, and there is a cortical-to-medullary gradient in heme biosynthesis, with greatest activity in the cortex and least in the medulla. This suggests that there are unique iron/heme metabolism features in some kidney cells, but the specific aspects of iron and heme metabolism in the kidney are yet to be explained. Iron represents a paradox for living systems by being essential for a wide variety of metabolic processes, but also having the potential to cause deleterious effects1.Cammack R. Wrigglesworth J.H. Baum H. Iron-dependent enzymes in mammalian systems,.in: Ponka P. Schulman H.M. Woodworth R.D. Iron Transport and Storage. CRC Press, Boca Raton1990: 17Google Scholar, 2.Richardson D.R. Ponka P. The molecular mechanisms of the metabolism and transport of iron in normal and neoplastic cells.Biochim Biophys Acta. 1997; 1331: 1-40Google Scholar, 3.Ponka P. Tissue-specific regulation of iron metabolism and heme synthesis: Distinct control mechanisms in erythroid cells.Blood. 1997; 89: 1-25Google Scholar, 4.Ponka P. Beaumont C. Richardson D.R. Function and regulation of transferrin and ferritin.Semin Hematol. 1998; 35: 35-54Google Scholar, 5.McCord J. Iron, free radicals and oxidative injury.Semin Hematol. 1998; 35: 5-12Google Scholar. On the one hand, iron is indispensable for life, serving as metal cofactor for many enzymes, either nonheme iron-containing proteins or hemoproteins. Hemoproteins are involved in a broad spectrum of crucial biologic functions, including oxygen binding (hemoglobins), oxygen metabolism (oxidases, peroxidase, catalases, etc.), and electron transfer (cytochromes). Many nonheme iron-containing proteins catalyze key reactions involved in energy metabolism (mitochondrial aconitase and [Fe-S] proteins of the electron transport chain) and DNA synthesis (ribonucleotide reductase). Moreover, iron-containing proteins are required for the metabolism of collagen, tyrosine, and catecholamines. On the other hand, chemical properties of iron that are so useful for an astonishing array of biological functions have created problems for living organisms. In solution, iron exists in two oxidation states, Fe(II) and Fe(III), which can donate or accept electrons, respectively. However, these redox reactions may become hazardous for the organism. At physiological pH and oxygen tension, Fe(II) is readily oxidized to Fe(III), which rapidly forms essentially insoluble Fe(OH)3 polymers. Moreover, unless appropriately chelated, iron, because of its catalytic action in one-electron redox reactions, plays a key role in the formation of harmful oxygen radicals that ultimately cause peroxidative damage to vital cell structures5.McCord J. Iron, free radicals and oxidative injury.Semin Hematol. 1998; 35: 5-12Google Scholar , 6.Halliwell B. Gutteridge J.M. Role of free radicals and catalytic metal ions in human disease: An overview.Methods Enzymol. 1990; 186: 1-85Google Scholar. Thus, organisms were compelled to solve one of the many paradoxes of life, that is, to keep "free iron" at the lowest possible level and yet in concentrations allowing its adequate supply for the synthesis of hemoproteins and other iron-containing molecules. This has been achieved by the evolution of specialized molecules for the acquisition, transport, and storage of iron in a soluble, nontoxic form to meet cellular and organismal iron requirements. Moreover, organisms are equipped with highly sophisticated mechanisms that coordinately regulate cellular iron uptake and storage and maintain iron in the intracellular labile pool at appropriate levels. The kidney, like other organs, requires iron for metabolic processes, and it is likely that iron deficiency or excess can cause disturbed function of kidney cells. Although little information is available on iron metabolism in kidney cells, they probably acquire most of their iron from plasma glycoprotein, transferrin. This review provides an overview of the molecular mechanisms involved in cellular iron uptake and metabolism, and an attempt is made to identify and discuss some specific aspects of iron and heme metabolism in the kidney. Physiologically, the majority of cells in the organism acquire iron from a well-characterized plasma glycoprotein, transferrin (approximately 80 kD)2.Richardson D.R. Ponka P. The molecular mechanisms of the metabolism and transport of iron in normal and neoplastic cells.Biochim Biophys Acta. 1997; 1331: 1-40Google Scholar , 4.Ponka P. Beaumont C. Richardson D.R. Function and regulation of transferrin and ferritin.Semin Hematol. 1998; 35: 35-54Google Scholar. Transferrin consists of two homologous domains, each of which contains one high-affinity Fe(III)-binding site. Affinity of iron to transferrin is a pH-dependent process. In plasma (pH approximately 7.4), transferrin binds iron very strongly (Kd approximately 10-23 mol/liter), whereas virtually no binding occurs at pH ≤ 4.5, and this property plays an important role in the physiological mechanism of iron release from transferrin (detailed later in this article). Transferrin binds iron via the phenolate oxygens of two tyrosine residues, an imidazole nitrogen of a histidine residue and a carboxylate oxygen of an aspartic acid residue7.Anderson B.F. Baker H.M. Norris G.E. Rice D.W. Baker E.N. Structure of human lactoferrin: Crystallographic structure analysis and refinement at 2.8 Å resolution.J Mol Biol. 1989; 209: 711-734Google Scholar. These protein ligands occupy four of the six octahedral sites around each iron atom, leaving two cis positions to be filled by the anion carbonate (or bicarbonate). Binding and release of iron by transferrin are accompanied by dramatic conformational changes in the protein. In the absence of iron, the two domains involved in the binding are widely separated and assume an "open" configuration. On the other hand, insertion of iron brings two domains of the binding cleft close toward the metal, and transferrin assumes "closed" conformational state8.Baker E.N. Lindley P.F. New perspectives on the structure and function of transferrin.J Inorg Biochem. 1992; 47: 147-160Google Scholar. Transferrin functions to transport iron between sites of absorption, storage, and use. Although the transferrin-to-cell branch of the metabolic iron cycle is reasonably well known (discussed later in this article), the mechanism and regulation of iron mobilization and transport from tissue stores to plasma transferrin are the least understood aspects of iron metabolism. Transferrin receives most of its iron from hemoglobin catabolized by macrophages of the reticuloendothelial system (for example, Kupffer cells). Senescent erythrocytes are internalized by the macrophages that liberate iron from its confinement within the protoporphyrin ring by the action of heme oxygenase9.Maines M.D. Heme Oxygenase: Clinical Applications and Functions. CRC Press, Boca Raton1992Google Scholar , 10.Maines M.D. The heme oxygenase system: A regulator of second messenger gases.Annu Rev Pharmacol Toxicol. 1997; 37: 517-554Google Scholar and then release iron almost quantitatively to transferrin in the circulation. Unfortunately, the mechanisms and controls involved in the release of iron from macrophages and other cells have not been defined. Interestingly, studies of patients with recently identified genetic deficiency of ceruloplasmin suggest that iron may be released from cells of many tissues, and not just the liver and macrophages as once thought. Ceruloplasmin is a blue copper-containing protein with ferroxidase activity, and patients with hereditary aceruloplasminemia have low plasma iron levels, but marked iron accumulation is evident in the liver, pancreas, brain, and also the kidney11.Yoshida K. Furihata K. Takeda S. Nakamura A. Yamamoto K. Morita H. Hiamuta S. Ikeda S. Shimizu N. Yanagisawa N. A mutation in the ceruloplasmin gene is associated with systemic hemosiderosis in humans.Nature Genet. 1995; 9: 267-272Google Scholar. One possible explanation of iron overload in aceruloplasminemic patients is that the release of iron from the cells requires the ferroxidase activity of ceruloplasmin. It is conceivable that ceruloplasmin may facilitate cellular iron release by promoting the oxidation of Fe(II), the redox form in which iron appears to be within the intracellular "transit" pool12.Breuer W. Epsztein S. Cabantchik Z.I. Iron acquired from transferrin by K562 cells is delivered into a cytoplasmic pool of chelatable iron(II).J Biol Chem. 1995; 270: 24209-24215Google Scholar. In this regard, it may be pertinent to mention that the yeast Saccharomyces cerevisiae possesses a membrane-spanning ferroxidase (Fet3) that has homology to the multicopper oxidases, including ceruloplasmin, and that is required for high-affinity iron transport13.Askwith C. Eide D. Van Ho A. Bernard P.S. Davis-Kaplan S. Sipe O.H. Kaplan J. The FET3 gene of S. cerevisiae encodes a multicopper oxidase required for ferrous iron uptake.Cell. 1994; 76: 403-410Google Scholar. Normally, plasma iron concentration is approximately 18 μmol/liter, and total iron-binding capacity (a measure of plasma transferrin levels) is approximately 56 μmol/liter; thus, transferrin is about one-third saturated with iron, with approximately 10% present as a diferric transferrin. In healthy adults, the total plasma iron pool (approximately 3 mg) remains remarkably constant despite being turned over more than 10-fold every day and is virtually unaffected by iron in stores (ferritin and hemosiderin) that can vary from 350 to 900 mg in females and males, respectively14.Bothwell T.A. Charlton R.W. Cook J.D. Finch C.A. Iron Metabolism in Man. Blackwell Scientific, Oxford1979Google Scholar. Hence, there seems to be a control mechanism that guarantees that the rate of iron release from stores perfectly matches the one with which the iron is taken up by tissues, but the nature of this regulation is unknown. Hemodialysis patients with normal or even increased iron in stores sometimes develop resistance to erythropoietin therapy15.Adamson J.W. The relationship of erythropoietin and iron metabolism to red blood cell production in humans.Semin Oncol. 1994; 21: 9-15Google Scholar. This condition is referred to as "functional iron deficiency" and is caused by an inadequate mobilization of ferritin iron during rapid hemoglobin regeneration. In patients with severe iron overload, plasma can contain transferrin completely saturated with iron and also a chelatable low molecular weight iron fraction not associated with transferrin16.Hershko C. Graham G. Bates G.W. Rachmilewitz E.A. Non-specific serum iron in thalassemia: Abnormal serum iron fraction of potential toxicity.Br J Haematol. 1978; 40: 255-263Google Scholar. Nonspecific, non-transferrin–bound iron is rapidly cleared from the plasma, mainly by the liver17.Craven C.M. Alexander J. Eldridge M. Kushner H.P. Bernstein S. Kaplan J. Tissue distribution and clearance kinetics of non-transferrin-bound iron in the hypotransferrinemic mouse: A rodent model for hemochromatosis.Proc Natl Acad Sci USA. 1987; 84: 3457-3461Google Scholar. However, there is also evidence for the occurrence of a non-transferrin–bound iron uptake system in renal cortex18.Bradbury M.W.B. Raja K. Veda I. Contrasting uptakes of 59Fe into spleen, liver, kidney and some soft tissues in normal and hypotransferrinaemic mice: Influence of an antibody against the transferrin receptor.Biochem Pharmacol. 1994; 47: 969-974Google Scholar. Although transferrin can be synthesized by many tissues, including lymph nodes and circulating lymphocytes, macrophages, bone marrow, spleen, thymus, salivary glands, mammary glands, and Sertoli cells of testis, the liver is the major source of plasma transferrin in adults2.Richardson D.R. Ponka P. The molecular mechanisms of the metabolism and transport of iron in normal and neoplastic cells.Biochim Biophys Acta. 1997; 1331: 1-40Google Scholar , 19.Morgan E.H. Transferrin, biochemistry, physiology and clinical significance.Mol Aspects Med. 1981; 4: 1-123Google Scholar. In mouse or rat fetuses, transferrin mRNA can be detected in kidney, and its content increases during fetal development up to birth and then rapidly decreases20.Zakin M.M. Regulation of transferrin gene expression.FASEB J. 1992; 6: 325-328Google Scholar. Hence, it is likely that transferrin is synthesized in fetal kidney, and it is tempting to speculate that it serves an important local function in providing iron for the growth and metabolism of cells during kidney development. The liver and kidneys account for approximately 50% of the total rate of transferrin catabolism. Catabolism of transferrin in the liver is probably the result of endocytotic uptake and lysosomal degradation, whereas that in the kidney is probably due to glomerular filtration followed by reabsorption and degradation by the renal tubules21.Straham M.E. Crowe A. Morgan E.H. Iron uptake in relation to transferrin degradation in brain and other tissues of rats.Am J Physiol. 1992; 263 (Regul Integrative Comp Physiol 32): R924-R929Google Scholar. Transferrin is recognized by specific cell membrane receptors that are gatekeepers responsible for physiological iron acquisition by most cell types in the organism2.Richardson D.R. Ponka P. The molecular mechanisms of the metabolism and transport of iron in normal and neoplastic cells.Biochim Biophys Acta. 1997; 1331: 1-40Google Scholar. The transferrin receptor consists of a disulfide-linked transmembrane glycoprotein homodimer having a molecular radius (Mr) of 180 kDa, and each subunit (90 kDa) binds one molecule of transferrin. The human transferrin receptor contains a small N-terminal cytoplasmic domain of hydrophilic character having a molecular mass of 5 kDa and frequently contains a phosphate group bound to the hydroxyl moiety of serine-24. However, the phosphorylation and dephosphorylation of this latter residue is not required for controlling endocytosis or recycling of the transferrin receptor. The cytoplasmic domain of the transferrin receptor is essential for receptor internalization, and a tetrapeptide sequence within the cytoplasmic tail of the transferrin receptor acts as a signal for high-efficiency endocytosis. The cytoplasmic tail is linked to a C-terminal extracellular domain of 672 amino acids by a hydrophobic membrane-spanning segment 62 amino acids from the N-terminus, and this hydrophobic part of the transferrin receptor contains covalently bound fatty acid residues (palmitic acid) as a result of post-translational modification2.Richardson D.R. Ponka P. The molecular mechanisms of the metabolism and transport of iron in normal and neoplastic cells.Biochim Biophys Acta. 1997; 1331: 1-40Google Scholar. In nonerythroid cells, transferrin receptor numbers correlate negatively with iron levels in an ill-defined "transit iron pool," and the regulation of the receptor synthesis is post-transcriptional and involves modulation of transferrin receptor mRNA stability (see later here). However, in erythroid cells, the primary control of transferrin receptor expression appears to be transcriptional, and the transcription probably plays an important role in maintaining high levels of receptor needed to support hemoglobinization3.Ponka P. Tissue-specific regulation of iron metabolism and heme synthesis: Distinct control mechanisms in erythroid cells.Blood. 1997; 89: 1-25Google Scholar. The reported association constants of transferrin for the receptor vary greatly (10-7 to 10-9 mol/liter), probably depending on conditions of measurement and cells used. The iron status of transferrin has an important effect on the affinity of transferrin for its receptor, with diferric transferrin having the greatest affinity, monoferric transferrins an intermediate affinity, and apotransferrin very low affinity22.Young S.P. Bomford A. Williams R. The effect of the iron saturation of transferrin on its binding and uptake by rabbit reticulocytes.Biochem J. 1984; 219: 505-510Google Scholar. As already mentioned, normal plasma transferrin concentration is approximately 50 μmol/liter, of which diferric transferrin constitutes approximately 10%. Because the association constant of diferric transferrin is 30- and 500-fold higher than those of monoferric and apotransferrin, respectively22.Young S.P. Bomford A. Williams R. The effect of the iron saturation of transferrin on its binding and uptake by rabbit reticulocytes.Biochem J. 1984; 219: 505-510Google Scholar, the delivery of iron to cells is predominantly by diferric transferrin. The concentration of diferric transferrin in normal plasma is adequate for saturating all cellular transferrin receptors with the ligand. The structural features of transferrin that are required for the interaction of transferrin with the receptor have not yet been established. Ferritin is a ubiquitous protein in which the only clearly defined function is the sequestration and storage of iron2.Richardson D.R. Ponka P. The molecular mechanisms of the metabolism and transport of iron in normal and neoplastic cells.Biochim Biophys Acta. 1997; 1331: 1-40Google Scholar , 23.Harrison P.M. Arosio P. Ferritin: Molecular properties, iron storage function and cellular regulation.Biochim Biophys Acta. 1996; 1275: 161-203Google Scholar. Mammalian ferritin consists of a protein shell that can accommodate up to 4,500 atoms of iron in its internal cavity. The molecular structure of horse spleen ferritin has been well characterized. The protein shell by itself has a molecular mass between 430 and 460 kDa, is approximately 25 Å thick, and is made up of 24 symmetrically related subunits of two types, a light subunit (L-subunit) of approximately 19 kDa and a heavy subunit (H-subunit) of approximately 21 kDa. The amino acid sequences of the H- and L-subunits differ by approximately 50%, and the ferritin genes from several species, including humans, have been cloned and sequenced23.Harrison P.M. Arosio P. Ferritin: Molecular properties, iron storage function and cellular regulation.Biochim Biophys Acta. 1996; 1275: 161-203Google Scholar. Different proportions of the two subunits give rise to the heterogeneity of ferritin observed in different tissues. The ferritin molecule has an internal diameter of 70 to 80 Å and an external diameter of 120 to 130 Å. The entry and exit of iron may occur via channels in the protein shell. There are six fourfold channels that are hydrophobic in nature and eight threefold channels that are hydrophilic, and all of these channels are approximately 3 to 4 Å in diameter23.Harrison P.M. Arosio P. Ferritin: Molecular properties, iron storage function and cellular regulation.Biochim Biophys Acta. 1996; 1275: 161-203Google Scholar. Once within the protein shell, iron is stored in the ferric state as ferric-oxyhydroxide phosphate of approximate composition (FeOOH)8 (FeO-OPO3H2), and as described earlier here, holoferritin can accommodate approximately 4500 atoms of iron, doubling its molecular mass to 900 kDa. Iron exchange with ferritin has been extensively studied in vitro. There is a consensus that relatively soluble ferrous iron, which is incorporated into the shell much more efficiently than ferric iron, is oxidized and deposited after its association with the inner surface of the subunits. Recombinant H-ferritin, as compared with recombinant L-chain, incorporates iron at rates several times greater, and this difference is likely caused by a ferroxidase center associated with the H-ferritin subunit that promotes the oxidation of Fe(II) to Fe(III). On the other hand, L-chain apoferritin has a higher capacity than the H-subunit to induce iron-core nucleation23.Harrison P.M. Arosio P. Ferritin: Molecular properties, iron storage function and cellular regulation.Biochim Biophys Acta. 1996; 1275: 161-203Google Scholar. Unfortunately, we know virtually nothing about the exchange of iron with ferritin in intact cells, and some evidence indicates that the degradation of the ferritin protein may be an important mechanism for the release of iron within the cell24.Pippard M.J. Tikerpae J. Peters T.J. Ferritin iron metabolism in the rat liver.Br J Haematol. 1986; 64 (abstract): 839Google Scholar. Ferritin synthesis is inducible by iron by a mechanism in which iron recruits ferritin mRNA from an inactive pool (discussed later in this article). In addition, inflammatory cytokines and "oxidative stress" are involved in an iron-independent regulation of ferritin translation, and transcriptional regulation of ferritin gene expression has been described4.Ponka P. Beaumont C. Richardson D.R. Function and regulation of transferrin and ferritin.Semin Hematol. 1998; 35: 35-54Google Scholar. Although the only well-defined function of ferritin is the storage and detoxification of intracellular nonfunctioning iron, it is known that small amounts of ferritin are present in the plasma. Ferritin was detected in the circulation of normal subjects about 25 years ago, but the origin and possible physiological role of plasma ferritin in normal individuals remain elusive. However, it is known that normal serum ferritin, in contrast to cellular ferritin, is partly glycosylated, suggesting that it is synthesized by the rough endoplasmic reticulum. It is generally believed that plasma ferritin has a low iron content, even in iron-overloaded individuals14.Bothwell T.A. Charlton R.W. Cook J.D. Finch C.A. Iron Metabolism in Man. Blackwell Scientific, Oxford1979Google Scholar, and further support for this was recently provided by Linder et al. These latter investigators have identified a number of other unexpected differences between plasma and tissue ferritin, suggesting the distinct nature of ferritin in the circulation. Moreover, it has been suggested that the serum ferritin may not be the product of the same genes as those encoding intracellular ferritin25.Linder M.C. Schaffer K.J. Hazegh-Azam M. Zhou C.Y. Tran T.N. Nagel G.M. Serum ferritin: Does it differ from tissue ferritin?.J Gastroenteric Hepatoid. 1996; 11: 1033-1036Google Scholar. The current view on iron acquisition via transferrin-receptor–mediated endocytosis, which is likely to be identical in all cell types, is schematically depicted in Figure 1 2.Richardson D.R. Ponka P. The molecular mechanisms of the metabolism and transport of iron in normal and neoplastic cells.Biochim Biophys Acta. 1997; 1331: 1-40Google Scholar, 3.Ponka P. Tissue-specific regulation of iron metabolism and heme synthesis: Distinct control mechanisms in erythroid cells.Blood. 1997; 89: 1-25Google Scholar, 4.Ponka P. Beaumont C. Richardson D.R. Function and regulation of transferrin and ferritin.Semin Hematol. 1998; 35: 35-54Google Scholar, 19.Morgan E.H. Transferrin, biochemistry, physiology and clinical significance.Mol Aspects Med. 1981; 4: 1-123Google Scholar. In the first step, transferrin attaches to specific receptors on the cell surface by a physicochemical interaction, not requiring temperature and energy. By a temperature- and energy-dependent process, the transferrin-receptor complexes are then internalized by the cells enclosed within endocytic vesicles. Iron is released from the transferrin within the endocytic vesicles by a temperature- and energy-dependent process that involves endosomal acidification26.Morgan E.H. Inhibition of reticulocyte iron uptake by NH4Cl and CH3NH2.Biochim Biophys Acta. 1981; 642: 119-134Google Scholar. An influx of protons into endosomes probably occurs via an adenosine triphosphate-dependent H+ pump that is, however, poorly defined. The minimum pH in endosomes (approximately 5.3) is not low enough to remove iron from both Fe-binding sites of transferrin, yet cells are capable of removing iron from transferrin with remarkable efficacy. This paradox has recently been explained by documenting that binding to cellular receptors promotes more efficient iron release from transferrin at mildly acidic pH27.Bali P.K. Zap O. Aileen P. A new role for the transferrin receptor in the release of iron from transferrin.Biochemistry. 1991; 30: 324-328Google Scholar. Iron transport across the endosomal membrane is poorly characterized and likely requires a specific transporter. One candidate for endosomal iron transporter is "natural resistance-associated macrophage protein-2," the mutation of which is a likely cause of decreased iron uptake by erythroid cells (and possibly other cells) of mice with microcytic anemia (mk/mk)28.Fleming M.D. Tremor III, C.C. Us M.A. Foenzler D. Beier D.R. Dietrich W.F. Andrews N.C. Microcytic anaemia mice have a mutation in Nramp2, a candidate iron transporter gene.Nature Genet. 1997; 16: 383-386Google Scholar and of anemic Belgrade (b/b) rats29.Fleming M.D. Romano M.A. Us M.A. Garrick L.M. Garrick M.D. Andrews M.C. Nramp2 is mutated in the anemic belgrade (b) rat: Evidence for a role for Nramp2 in endosomal iron transport.Proc Natl Acad Sci USA. 1998; 95: 1148-1153Google Scholar. Interestingly, natural resistance-associated macrophage protein-2 appears to be involved in intestinal iron transport as well28.Fleming M.D. Tremor III, C.C. Us M.A. Foenzler D. Beier D.R. Dietrich W.F. Andrews N.C. Microcytic anaemia mice have a mutation in Nramp2, a candidate iron transporter gene.Nature Genet. 1997; 16: 383-386Google Scholar , 30.Gunshin H. Mackenzie B. Berger U.V. Gunshin Y. Romero M.F. Boron W.F. Nussberger S. Gallan J.L. Hediger M.A. Cloning and characterization of a mammalian proton-coupled metal-ion transporter.Nature. 1997; 388: 482-488Google Scholar, and further research is needed to determine its precise cellular localization in various cell types. Iron, probably complexed with an as yet unidentified ligand, is then transported to intracellular sites of use and/or storage in ferritin. This aspect of iron metabolism, including the nature of the elusive intermediary pool of iron and its cellular trafficking, remains enigmatic. Only in erythroid cells does some evidence exist for a specific targeting of iron toward mitochondria2.Richardson D.R. Ponka P. The molecular mechanisms of the metabolism and transport of iron in normal and neoplastic cells.Biochim Biophys Acta. 1997; 1331: 1-40Google Scholar, 3.Ponka P. Tissue-specific regulation of iron metabolism and heme synthesis: Distinct control mechanisms in erythroid cells.Blood. 1997; 89: 1-25Google Scholar, 31.Richardson D.R. Ponka P. Vyoral D. Distribution of iron in reticulocytes after inhibition of heme synthesis with succinylacetone: Examination of cytoplasmic and mitochondrial intermediates involve
Referência(s)