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ScienceWeek
CELL BIOLOGY: ON IRON HOMEOSTASIS
The following points are made by Ernest Beutler (Science 2004 306:2051):
1) Due to its unique chemical properties, iron plays a central role in biology. Although iron is vital for life, it is highly reactive and so can be toxic when in excess. Evolution has thus developed mechanisms to regulate the amount of iron in the cells of our body. Painstaking studies of iron balance in humans 65 years ago showed that virtually no iron is excreted and that stable iron levels are maintained by modulating absorption of iron from the gut [1]. Iron homeostasis is complex, as there are many different proteins that respond not only to the total body burden of iron, but also to stimuli such as hypoxia, anemia, and inflammation.
2) There are two very different aspects to iron homeostasis. First, iron modulates the synthesis of a variety of proteins involved in iron metabolism, including the iron storage protein ferritin, the iron transporter transferrin, and the transferrin receptor. Second, another group of proteins regulates the transport of iron into and out of cells. In response to iron deficiency, hypoxia, or anemia, more iron is transported out of the gut lumen into intestinal epithelial cells, and then from the intestinal epithelia and liver macrophages (in the form of iron recycled from hemoglobin) into the blood. Inflammation and iron overload have the opposite effect, decreasing the amount of iron absorbed from the gut and released into the blood. The regulation of iron metabolism proteins by iron and the control of iron transport are undoubtedly connected, but how? New work [2,3] sheds light on these processes.
3) More than 15 years ago, elegant studies by Hentze, Rouault, Klausner, and their associates established the existence of RNA motifs called iron responsive elements (IRE) in numerous transcripts of genes involved in iron metabolism and homeostasis.[4-6] These motifs are bound by iron regulatory proteins 1 and 2 (IRP1 and IRP2) depending on cellular iron levels. When these proteins bind to IRE motifs in the 5'-untranslated region of, for example, the ferritin mRNA transcript, translation of the transcript is blocked and synthesis of ferritin is halted. In contrast, when IRP1 and IRP2 bind to the IRE in the 3'-untranslated region of, for example, the transferrin receptor transcript, the transcript is stabilized, translation proceeds, and the transferrin receptor is synthesized.
4) Evolution has generously provided two IRPs, both of which bind to IREs but sense iron in very different. IRP1 is a bifunctional cytosolic protein that contains an iron-sulfur cluster. In the presence of iron, IRP1 acts as an aconitase (interconverting citrate and isocitrate), but in the absence of iron, IRP1 binds to the IREs of various iron homeostasis transcripts with high affinity. By contrast, IRP2 undergoes iron-dependent degradation in iron-replete cells and therefore is not available to bind to the IREs. But things are a little more complicated than this. IRP2 is also sensitive to degradation in the presence of nitric oxide (NO), whereas IRP1 is activated by NO [2]. It had been presumed that IRP1 is the principal iron sensor and a major player in iron homeostasis, yet mice deficient in IRP1 appear normal. In contrast, mice deficient in IRP2 show pronounced misregulation of iron metabolism and nerve damage.
References (abridged):
1. R. A. McCance, E. M. Widdowson, Lancet ii, 680 (1937)
2. E. G. Meyron-Holtz, M. C. Ghosh, T. A. Rouault, Science 306, 2087 (2004)
3. E. Nemeth et al., Science 306, 2090 (2004)
4. T. A. Rouault, Blood Cells Mol. Dis. 29, 309 (2002)
5. T. Rouault, R. Klausner, Curr. Top. Cell Regul. 35, 1 (1997)
6. M. W. Hentze, L. C. Kuhn, Proc. Natl. Acad. Sci. U.S.A. 93, 8175 (1996)
Science http://www.sciencemag.org
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CELL BIOLOGY: IRON AND BIOLOGICAL CELLS
The following points are made by J. Barasch and K. Mori (Nature 2004 432:811):
1) Iron is a problem for all that live by it. This is because the ferrous ion, although soluble in biological fluids, generates toxic hydroxyl radicals in the presence of oxygen. The oxidized (ferric) form is better behaved, but it is insoluble in water at neutral pH [2], producing ferrihydroxide precipitates; ferri-phosphate precipitates also form with the biologically abundant phosphate ion. It is somewhat paradoxical that these iron ions are so inaccessible, given that iron is the key catalytic site of many of the enzymes and gas-transporting proteins in cells.
2) To solve the problem of taking up iron into cells, organisms have developed numerous iron-solubilization technologies. In mammals, birds, fish and amphibians, a highly conserved protein called "transferrin" is needed to move the major load of extracellular iron into cells. Transferrin binds extracellular iron with high affinity (10^(-20) M), docks at transferrin receptors on the cell membrane, and is taken up into cells by means of the invagination of sections of this membrane. The iron is then unloaded from transferrin into specialized intracellular compartments, from where it can be transferred to the cytoplasm.
3) In bacteria and fungi, meanwhile, other iron-capturing tools are brought into play. For instance, these organisms can secrete and then reclaim a bewildering array of iron-avid peptides and ester derivatives, known collectively as "siderophores"[3]. These are classified as phenolates-catecholates or hydroxamates, or mixtures of the two forms. Enterochelin, a major catecholate siderophore, chelates iron with extraordinarily high affinity (10^(-49) M) [4], docks at unique receptors -- the Fep proteins -- on the bacterial surface, and is destroyed by esterases after being internalized.
4) So what happens when bacteria grow in a host that also covets iron (mammalian blood serum has just 10^(-26) M free iron[5]), or when two microorganisms compete for the same source of metal? Essentially, thievery reigns. For instance, when in competition with fungi, bacteria can hijack iron that is targeted to the fungi by producing receptors for fungal siderophores that the bacteria themselves do not make. When in competition with animal hosts, bacteria can expropriate transferrin (or the related lactoferrin) wholesale, or simply remove its iron by using siderophores. Mycobacteria use the siderophore carboxymycobactin to strip iron from mammalian ferritin, another iron-binding protein. And fungi of the genus Rhizopus have been reported to capture an iron-chelating medicine, deferoxamine, allowing these organisms to multiply to levels that are disastrous for the host. Perhaps it is not surprising that giving iron to patients and to mice worsens the outcome of bacterial and mycobacterial infections.[1]
References (abridged):
1. Flo, T. H. et al. Nature 432, 917-921 (2004)
2. Klausner, R. D. & Rouault, T. Harvey Lect. 92, 99-112 (1996-97)
3. Neilands, J. B. J. Biol. Chem. 270, 26723-26726 (1995)
4. Loomis, L. D. & Raymond, K. N. Inorg. Chem. 30, 906-911 (1991)
5. Otto, B. R. et al. Infect. Immun. 59, 2999-3003 (1991)
Nature http://www.nature.com/nature
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ON THE EFFECTS OF IRON DEFICIENCY AND IRON EXCESS
The following points are made by P.B. Walter et al (Proc. Nat. Acad. Sci. 2002 99:2264):
1) Iron deficiency is the most common nutritional deficiency worldwide, affecting approximately 2 billion people, mostly women and children. In the US, an estimated 9 million people are iron deficient. Iron deficiency is a significant public health concern associated with an increased risk of poor pregnancy outcomes and impaired cognitive development in young children. Pregnant women in developing countries are commonly given daily supplements containing 120 milligrams of iron to prevent and correct gestational iron deficiency. This dose of iron, which is 10 times the normal daily dietary iron intake, can cause gastrointestinal side effects.
2) The authors have already reported that equivalent doses of daily high-iron supplements in rats (i.e., 10 x normal intake, 8000 micrograms iron per day) results in an abnormal accumulation of intestinal mucosal and hepatic non-heme iron and significant increases in lipid peroxidation. The authors unexpectedly observed that iron-deficient rats also had markedly increased lipid peroxidation, suggesting that both iron deficiency and iron excess promote oxidative stress.
3) The increased oxidative stress observed in both iron deficiency and excess may involve mitochondrial dysfunction, as has been observed in aging and associated degenerative diseases. Mitochondria use 90 percent of inspired oxygen, produce a significant amount of cellular superoxide, and accumulate iron for heme and iron-sulfur cluster formation. Studies of severe iron overload modeling hemochromatosis have reported increased hepatic lipid peroxidation, nuclear DNA damage, and mitochondrial dysfunction. The severe iron overload of mitochondria has been found to induce mitochondrial DNA damage, and such damage correlates with the mitochondrial dysfunction associated with oxidant stress and aging.
4) The authors now report that both inadequate and excessive iron (10 x nutritional need) cause significant mitochondrial malfunction. Although excess iron has been known to cause oxidative damage, the observation of oxidant-induced damage to mitochondria from iron deficiency has been unrecognized previously. In summary, the authors suggest that untreated iron deficiency, as well as excessive iron supplementation, are deleterious, emphasizing the importance of maintaining optimal iron intake.
Proc. Nat. Acad. Sci. http://www.pnas.org
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