Cytosolic Aconitase and Ferritin Are Regulated by Iron inCaenorhabditis elegans

Abstract

Iron regulatory protein-1 (IRP-1) is a cytosolic RNA-binding protein that is a regulator of iron homeostasis in mammalian cells. IRP-1 binds to RNA structures, known as iron-responsive elements, located in the untranslated regions of specific mRNAs, and it regulates the translation or stability of these mRNAs. Iron regulates IRP-1 activity by converting it from an RNA-binding apoprotein into a [4Fe-4S] cluster protein exhibiting aconitase activity. IRP-1 is widely found in prokaryotes and eukaryotes. Here, we report the biochemical characterization and regulation of an IRP-1 homolog in Caenorhabditis elegans(GEI-22/ACO-1). GEI-22/ACO-1 is expressed in the cytosol of cells of the hypodermis and the intestine. Like mammalian IRP-1/aconitases, GEI-22/ACO-1 exhibits aconitase activity and is post-translationally regulated by iron. Although GEI-22/ACO-1 shares striking resemblance to mammalian IRP-1, it fails to bind RNA. This is consistent with the lack of iron-responsive elements in the C. elegans ferritin genes, ftn-1 and ftn-2. While mammalian ferritin H and L mRNAs are translationally regulated by iron, the amounts of C. elegans ftn-1 and ftn-2 mRNAs are increased by iron and decreased by iron chelation. Excess iron did not significantly alter worm development but did shorten their life span. These studies indicated that iron homeostasis in C. elegans shares some similarities with those of vertebrates. Iron regulatory protein-1 (IRP-1) is a cytosolic RNA-binding protein that is a regulator of iron homeostasis in mammalian cells. IRP-1 binds to RNA structures, known as iron-responsive elements, located in the untranslated regions of specific mRNAs, and it regulates the translation or stability of these mRNAs. Iron regulates IRP-1 activity by converting it from an RNA-binding apoprotein into a [4Fe-4S] cluster protein exhibiting aconitase activity. IRP-1 is widely found in prokaryotes and eukaryotes. Here, we report the biochemical characterization and regulation of an IRP-1 homolog in Caenorhabditis elegans(GEI-22/ACO-1). GEI-22/ACO-1 is expressed in the cytosol of cells of the hypodermis and the intestine. Like mammalian IRP-1/aconitases, GEI-22/ACO-1 exhibits aconitase activity and is post-translationally regulated by iron. Although GEI-22/ACO-1 shares striking resemblance to mammalian IRP-1, it fails to bind RNA. This is consistent with the lack of iron-responsive elements in the C. elegans ferritin genes, ftn-1 and ftn-2. While mammalian ferritin H and L mRNAs are translationally regulated by iron, the amounts of C. elegans ftn-1 and ftn-2 mRNAs are increased by iron and decreased by iron chelation. Excess iron did not significantly alter worm development but did shorten their life span. These studies indicated that iron homeostasis in C. elegans shares some similarities with those of vertebrates. iron regulatory protein iron-responsive element untranslated region nematode growth medium ferric ammonium citrate deferoxamine green fluorescent protein Iron is an essential element required for growth and survival of most organisms. The importance of iron is implicit in the role it plays in oxygen transport and heme synthesis as well as its ability to serve as a cofactor for enzymes involved in a variety of biological processes including DNA synthesis, energy production, and neurotransmitter synthesis. Abnormally high concentration of cellular iron is toxic due to its ability to catalyze the generation of free radicals that damage DNA, lipids, and proteins. In humans, the accumulation of excess cellular iron can result in cirrhosis, arthritis, cardiomyopathy, diabetes mellitus, and increased risk of cancer and heart disease. To provide adequate iron for cellular needs yet prevent the accumulation of excess iron, the concentration of iron within cells is tightly controlled. In vertebrates, the iron regulatory proteins 1 and 2 (IRP-1 and IRP-2)1 regulate iron homeostasis. IRPs are cytosolic RNA-binding proteins that regulate the translation or the stability of mRNAs encoding proteins involved in iron and energy homeostasis (1Hentze M.W. Kühn L.C. Proc. Natl. Acad. Sci. U. S. A. 1996; 93: 8175-8182Google Scholar, 2Eisenstein R.S. Annu. Rev. Nutr. 2000; 20: 627-662Google Scholar, 3Schneider B.S. Leibold E.A. Curr. Opin. Clin. Nutr. Metab. Care. 2000; 3: 267-273Google Scholar, 4Theil E.C. Eisenstein R.S. J. Biol. Chem. 2000; 275: 40659-40662Google Scholar). IRPs bind to RNA stem-loop structures, known as iron-responsive elements (IREs), that are located in either the 5′- or 3′-untranslated regions (UTRs) of specific mRNAs. These mRNAs encode proteins involved in iron storage (ferritin), iron utilization (erythroid aminolevilunate synthase and mitochondrial aconitase), and iron transport (transferrin receptor and divalent metal transporter-1). When iron is scarce, IRP binding to the 5′ IRE in ferritin mRNA represses translation, whereas IRP binding to the 3′ IREs in the transferrin receptor mRNA stabilizes this mRNA. When iron is abundant, IRPs lose affinity for the IREs, leading to enhanced ferritin synthesis and to the rapid degradation of transferrin receptor mRNA. By regulating the amount of iron taken up by transferrin receptor and the amount of iron sequestered by ferritin, cellular iron concentration is maintained, and iron toxicity is avoided. Iron regulates the RNA binding activity of IRP-1 and IRP-2, but the mechanism of regulation differs. In the presence of iron, a [4Fe-4S] cluster assembles in IRP-1, converting it from an RNA-binding protein into a cytosolic aconitase. Aconitases are [4Fe-4S] cluster proteins that are found in the cytosol, mitochondria, and glyoxysomes and catalyze the reversible isomerization of citrate and isocitrate viacis-aconitate (5Gruer M.J. Artymiuk P.J. Guest J.R. Trends Biochem. Sci. 1997; 22: 3-6Google Scholar). Despite information regarding the role of aconitase in mitochondria and in the glyoxylate cycle in microorganisms and plants, the function of cytosolic aconitase in higher eukaryotes is not clear. Unlike IRP-1, IRP-2 lacks a [4Fe-4S] cluster and consequently lacks aconitase activity (6Guo B., Yu, Y. Leibold E.A. J. Biol. Chem. 1994; 269: 24252-24260Google Scholar). Rather, iron regulation of IRP-2 involves iron-induced IRP2 degradation by the proteasome (7Guo B. Phillips J.D., Yu, Y. Leibold E.A. J. Biol. Chem. 1995; 270: 21645-21651Google Scholar, 8Iwai K. Klausner R.D. Rouault T.A. EMBO J. 1995; 14: 5350-5357Google Scholar, 9Iwai K. Drake S.K. Wehr N.B. Weissman A. LaVaute T. Minato N. Klausner R.D. Levine R.L. Rouault T.A. Proc. Natl. Acad. Sci. U. S. A. 1998; 95: 4924-4928Google Scholar). IRP-1s have been identified in a wide variety of organisms, including bacteria (10Prodromou C. Artymiuk P.J. Guest J.R. Eur. J. Biochem. 1992; 204: 599-609Google Scholar, 11Alen C. Sonenshein A.L. Proc. Natl. Acad. Sci. U. S. A. 1999; 96: 10412-10417Google Scholar, 12Mengaud J.M. Horwitz M.A. J. Bacteriol. 1993; 175: 5666-5676Google Scholar), plants (13Peyret P. Perez P. Alric M. J. Biol. Chem. 1995; 270: 8131-8137Google Scholar, 14Hayashi M. DeBellis L. Alpi A. Nishimura M. Plant Cell Physiol. 1995; 36: 669-680Google Scholar, 15Navarre D.A. Wendehenne D. Durner J. Noad R. Klessig D.F. Plant Physiol. 2000; 122: 573-582Google Scholar), and animals (16Muckenthaler M. Gunkel N. Frishman D. Cyrklaff A. Tomancak P. Hentze M.W. Eur. J. Biochem. 1998; 254: 230-237Google Scholar, 17Saas J. Ziegelbauer K. von Haeseler A. Fast B. J. Biol. Chem. 2000; 275: 2745-2755Google Scholar). IRP-1s share a high degree of amino acid identity among different species. For example, mammalian IRP-1s are >90% identical and are highly homologous to IRP-1s from other organisms, includingCaenorhabditis elegans (64% identity) (16Muckenthaler M. Gunkel N. Frishman D. Cyrklaff A. Tomancak P. Hentze M.W. Eur. J. Biochem. 1998; 254: 230-237Google Scholar),Arabidopsis thaliana (59% identity) plants (13Peyret P. Perez P. Alric M. J. Biol. Chem. 1995; 270: 8131-8137Google Scholar),Trypanosome brucei (64% identity) (17Saas J. Ziegelbauer K. von Haeseler A. Fast B. J. Biol. Chem. 2000; 275: 2745-2755Google Scholar), andEscherichia coli (52% identity) (10Prodromou C. Artymiuk P.J. Guest J.R. Eur. J. Biochem. 1992; 204: 599-609Google Scholar). In contrast, IRP-1s share only ∼20% amino acid identity to mitochondrial aconitases. Although these IRP-1s show striking similarity to mammalian IRP-1 and in most cases exhibit aconitase activity, only vertebrate and insect IRP-1s (18Rothenberger S. Mullner E.W. Kühn L.C. Nucleic Acids Res. 1990; 18: 1175-1179Google Scholar, 19Kohler S.A. Henderson B.R. Kuhn L.C. J. Biol. Chem. 1995; 270: 30781-30786Google Scholar, 20Gray N.K. Pantopoulous K. Dandekar T. Ackrell B.A. Hentze M.W. Proc. Natl. Acad. Sci. U. S. A. 1996; 93: 4925-4930Google Scholar, 21Zhang D. Albert D.W. Kohlhepp P., D- Pham D.Q. Winzerling J.J. Insect Mol. Biol. 2001; 10: 531-539Google Scholar) bind RNA. Exceptions are Bacillus subtilisand Plasmodium falciparum IRP-1s, where studies show that these proteins are capable of binding to a mammalian consensus IRE (11Alen C. Sonenshein A.L. Proc. Natl. Acad. Sci. U. S. A. 1999; 96: 10412-10417Google Scholar,22Loyevsky M. LaVaute T. Allerson C.R. Stearman R. Kassim O.O. Cooperman S. Gordeuk V.R. Rouault T.A. Blood. 2001; 15: 2555-2562Google Scholar). Here, we report on the biochemical properties and regulation ofC. elegans cytosolic aconitase (GEI-22/ACO-1). C. elegans is a multicellular organism that shares many basic cellular mechanisms with vertebrates, and consequently, it has been used to study development, neurobiology, stress, and aging. Many of the same genes that are involved in iron and energy homeostasis in vertebrates are conserved in C. elegans, including aconitases, ferritin, divalent metal transporter-1, frataxin, and iron sulfur cluster assembly proteins, suggesting that iron and energy homeostasis are also conserved. These features prompted us to characterize the biochemical properties and the regulation of GEI-22/ACO-1 and mechanisms regulating iron homeostasis in C. elegans. Wild-type C. elegans (variety Bristol, strain N2) on nematode growth medium or in with coli strain S. Scholar). For in medium bacteria and the bacteria medium with ferric ammonium citrate or deferoxamine an iron the of it to for with and and free of bacteria by The toxic concentration of and by iron toxicity and by growth of in different by worm RNA for from by of J. J. The Caenorhabditis elegans. Scholar). on with and to or for by with of bacteria to For iron toxicity life on with the to a and as to or with in a for in survival by the of iron. C. elegans from RNA from and and an by the of and a the of region in with a a and These on the of the GEI-22/ACO-1 amino acid from the with those of other IRP-1s the The into the of the mammalian green fluorescent protein by and the into the of the This of 5′ regulatory and of and in to The lacks encoding the amino of and the in a with DNA a for and by their and the same the of and the into of the into strain J. Biol. Chem. 1993; Scholar). in medium into acid and to an of to the for to GEI-22/ACO-1 and the in a by with and the The with of acid for 1 The into a and with GEI-22/ACO-1 with and GEI-22/ACO-1 1 For GEI-22/ACO-1 by The protein a of and the GEI-22/ACO-1 and used to The a on with a of to the of the mRNA. did not this of cells with of and 2 of The cells to and either or or The cells for and in of 1 a The for and the for protein the from or The free of bacteria by and in a of a The on a for The for 1 and the for protein the protein RNA-binding as E.A. Proc. Natl. Acad. Sci. U. S. A. Scholar), protein from or C. elegans and ferritin J. Biol. Chem. 1993; Scholar) or a C. elegans RNA. The ftn-2 RNA from DNA that to 5′ to the elegans The a by of ftn-2 and the the 5′ to the of the for to the for by the of of for used to the from and from cells with activity by the of to of protein in of aconitase J. Biol. Chem. Scholar). The of For aconitase in The and by from cells and by and the protein with the IRP-1 (6Guo B., Yu, Y. Leibold E.A. J. Biol. Chem. 1994; 269: 24252-24260Google Scholar), and IRP-2 (6Guo B., Yu, Y. Leibold E.A. J. Biol. Chem. 1994; 269: 24252-24260Google Scholar). The used the RNA from on or for in a RNA a and to a The with C. elegans DNA by the of worm DNA for by in The in of for 1 by a The to a of the and and for from of the C. elegans and ftn-2 and and by the DNA from on and the DNA and the DNA DNA with for and with and by The C. elegans aconitase genes, are and a protein that shares identity with mammalian IRP-1 (16Muckenthaler M. Gunkel N. Frishman D. Cyrklaff A. Tomancak P. Hentze M.W. Eur. J. Biochem. 1998; 254: 230-237Google Scholar), D. and (16Muckenthaler M. Gunkel N. Frishman D. Cyrklaff A. Tomancak P. Hentze M.W. Eur. J. Biochem. 1998; 254: 230-237Google Scholar), and A. thaliana (13Peyret P. Perez P. Alric M. J. Biol. Chem. 1995; 270: 8131-8137Google Scholar) and T. J. Ziegelbauer K. von Haeseler A. Fast B. J. Biol. Chem. 2000; 275: 2745-2755Google Scholar) IRP-1s only identity to L. M.A. J. Biol. Chem. 1990; Scholar) elegans mitochondrial a protein that shares identity to and mitochondrial aconitases. To study the iron homeostasis in C. elegans, by from the C. elegans GEI-22/ACO-1 required for aconitase activity, including the that serve as for the [4Fe-4S] cluster Proc. Natl. Acad. Sci. U. S. A. Scholar, Scholar, 1992; Scholar). GEI-22/ACO-1 also that are to those identified in mammalian IRP-1 in RNA including amino and Rouault T.A. Klausner R.D. Proc. Natl. Acad. Sci. U. S. A. 1994; Scholar, P. R. Kuhn L.C. EMBO J. 1999; 18: Scholar). The of GEI-22/ACO-1 in that of 5′ regulatory and of and to 2 This lacks and those encoding the amino and animals the high of cytosolic in the cells and in the in cells or in IRP-1 exhibits the of RNA binding and aconitase. Iron IRP-1 to from an RNA-binding apoprotein to a binding aconitase a [4Fe-4S] The these in IRP-1 protein GEI-22/ACO-1 amino acid identity with mammalian IRP-1, we GEI-22/ACO-1 binds RNA. The 5′ the C. elegans genes encoding elegans and elegans and for IREs, 5′ IREs are found in homologous genes in other S.A. Henderson B.R. Kuhn L.C. J. Biol. Chem. 1995; 270: 30781-30786Google Scholar, E.A. J. Biol. Chem. Scholar, M.W. Rouault T.A. A. Klausner R.D. Scholar, L. Biochem. 1992; Scholar). consensus IREs identified in these that IREs in the of these To for IRE binding activity in of in or the iron to located of the of the and C. elegans and are in vertebrates T. K. T. J.R. C. Scholar), we that these genes within these in or studies that and can and IRP-1 RNA binding activity (1Hentze M.W. Kühn L.C. Proc. Natl. Acad. Sci. U. S. A. 1996; 93: 8175-8182Google Scholar, 2Eisenstein R.S. Annu. Rev. Nutr. 2000; 20: 627-662Google Scholar, 4Theil E.C. Eisenstein R.S. J. Biol. Chem. 2000; 275: 40659-40662Google Scholar). The concentration of and on the growth of in different of and that specific RNA binding activity in worm by with the or with other C. elegans not GEI-22/ACO-1 in these by an cells with or and IRP RNA binding activity R. IRE increased IRP RNA binding activity as whereas on IRP RNA binding activity due to the high iron concentration in these cells. with a R. IRE in worm C. elegans with R. IRP-1 that R. IRE to R. IRP-1, that an of RNA binding activity not in these not To that GEI-22/ACO-1 lacks RNA binding activity, we expressed GEI-22/ACO-1 in a The of is that not with the of amounts of RNA binding activity. IRP-1 and IRP-2 also for RNA binding activity. the of IRP-1, and R. IRP-2, but only R. IRP-1 and R. IRP-2 to the R. IRE and these that GEI-22/ACO-1 not bind to a mammalian consensus IRE or to C. elegans that to The that GEI-22/ACO-1 lacks RNA binding activity. The in mitochondrial Proc. Natl. Acad. Sci. U. S. A. Scholar, Scholar, 1992; Scholar) are in suggesting that GEI-22/ACO-1 is an aconitase. To GEI-22/ACO-1 exhibits aconitase activity and it is regulated by iron, aconitase activity in cells with GEI-22/ACO-1 or cells with either or for aconitase activity. with GEI-22/ACO-1 a in aconitase activity with cells When cells with aconitase activity increased in cells with cells. aconitase activity did not significantly in cells with that these cells are and that the of IRP-1 is in the aconitase In contrast, aconitase activity in and cells. The decreased aconitase activity in cells is due to decreased cytosolic and mitochondrial aconitase GEI-22/ACO-1 expressed in suggesting that the in aconitase activity due to the of the apoprotein to the [4Fe-4S] The that iron a in aconitase activity in cells with cells that iron is of these that GEI-22/ACO-1 is an aconitase and that this activity can regulated by iron. To are regulated by iron in aconitase activity in from for in with either or and these the of iron In these aconitase activity and the cytosol with mitochondrial proteins. aconitase activity from in a in with that the amount of GEI-22/ACO-1 did not in or Although we the in aconitase activity to GEI-22/ACO-1 of these indicated that aconitase activity can regulated by iron in The also that the in aconitase activity in in is not as as in cells with GEI-22/ACO-1 This due to into in with into cells. The lack of IREs in the C. elegans and the of GEI-22/ACO-1 RNA binding activity that C. elegans ferritin genes by mechanisms other C. elegans proteins, we C. elegans and elegans and are homologous to R. and to R. and and proteins that are of R. P. 1996; Scholar). To ftn-1 and ftn-2 mRNAs are regulated by iron, on with or with for and ftn-1 and ftn-2 mRNAs by mRNA as concentration from to whereas a but is for In in the presence of ftn-1 mRNAs and To in ftn-1 and ftn-2 mRNAs, to mRNA These indicated that ftn-1 mRNAs are regulated by iron but is to in iron concentration ftn-2. mRNA not significantly with or is consistent with the amounts of GEI-22/ACO-1 protein are not by iron is known iron homeostasis in we the concentration of iron that toxicity in we the development of by iron. on into within that iron did not worm development not the life of on iron on with and that the life of on and and with for on These indicated that excess iron not the development of but is toxic are to iron their Here, we the regulation of GEI-22/ACO-1 and the regulation of iron homeostasis in C. elegans. show that GEI-22/ACO-1 is to other vertebrate IRP-1 proteins in that it exhibits aconitase activity and is post-translationally regulated by iron. Unlike vertebrate IRP-1 proteins, GEI-22/ACO-1 not bind RNA. show that GEI-22/ACO-1 is expressed in and are that and and is consistent with its role in energy homeostasis. show that high of iron the life of we that iron regulates the amounts of ftn-1 and ftn-2 mRNAs, in vertebrates, where ferritin H and L mRNAs are regulated by translation by the Aconitases are conserved [4Fe-4S] cluster proteins found in prokaryotes and eukaryotes that catalyze the reversible isomerization of citrate and isocitrate in the and glyoxylate Aconitases can into (5Gruer M.J. Artymiuk P.J. Guest J.R. Trends Biochem. Sci. 1997; 22: 3-6Google Scholar). is by IRP-1, shares identity with mammalian IRP-1, whereas the other is by mitochondrial shares only identity with GEI-22/ACO-1 and other IRP are to vertebrate IRP-1s, are RNA-binding proteins, it that GEI-22/ACO-1 also binds RNA. show that GEI-22/ACO-1 lacks RNA binding activity, is consistent with the lack of IREs in the C. elegans IRP-1s, as T. brucei (17Saas J. Ziegelbauer K. von Haeseler A. Fast B. J. Biol. Chem. 2000; 275: 2745-2755Google thaliana (13Peyret P. Perez P. Alric M. J. Biol. Chem. 1995; 270: 8131-8137Google Scholar), and D.A. Wendehenne D. Durner J. Noad R. Klessig D.F. Plant Physiol. 2000; 122: 573-582Google Scholar), to aconitases, but RNA binding activity not and it is that these proteins also not bind RNA. some IRP-1s bind RNA. For example, P. falciparum IRP-1 to bind a mammalian consensus IRE M. LaVaute T. Allerson C.R. Stearman R. Kassim O.O. Cooperman S. Gordeuk V.R. Rouault T.A. Blood. 2001; 15: 2555-2562Google Scholar), and B. aconitase binds not only to a mammalian consensus IRE but also to stem-loop in genes (11Alen C. Sonenshein A.L. Proc. Natl. Acad. Sci. U. S. A. 1999; 96: 10412-10417Google Scholar). these are in is not clear. these studies show that RNA binding is not a of the IRP-1 Iron post-translationally regulates GEI-22/ACO-1 activity. In and increased and decreased aconitase activity, In aconitase activity in in with and have on the amounts of GEI-22/ACO-1 protein or this that iron regulates GEI-22/ACO-1 activity by the assembly and of the [4Fe-4S] These studies also show that the [4Fe-4S] cluster in cells is in a cluster in Although we the in aconitase activity to GEI-22/ACO-1 of with mitochondrial the indicated that the iron concentration in regulate aconitase activity. show that in in the presence of the in aconitase activity in cells with The for these are not but we that in in not as as into cells. Despite information regarding the role of aconitase in mitochondria and in the glyoxylate the function of cytosolic aconitase in higher eukaryotes is not clear. The glyoxylate in plants and these to to for the synthesis of In plants, IRP-1 in the glyoxylate M. DeBellis L. Alpi A. Nishimura M. Plant Cell Physiol. 1995; 36: 669-680Google Scholar, R. Biochem. J. 1993; Scholar), where its with the growth of and with the in activity of other glyoxylate enzymes M. DeBellis L. Alpi A. Nishimura M. Plant Cell Physiol. 1995; 36: 669-680Google Scholar). study that aconitase with other glyoxylate and cycle enzymes are increased in A. thaliana suggesting a role for aconitase in M. K. T. M. J. Biol. Chem. Scholar). In T. IRP-1 is in cycle enzymes also (17Saas J. Ziegelbauer K. von Haeseler A. Fast B. J. Biol. Chem. 2000; 275: 2745-2755Google Scholar). IRP-1 in a glyoxylate in T. brucei is In the role of IRP-1 to in of iron excess R. M. J. Biol. Chem. 2000; 275: Scholar). some studies have that the glyoxylate in of stress, as 1998; Scholar) and A. this has yet to the glyoxylate cycle is in C. elegans B.A. Biochem. B.A. Scholar), it is that GEI-22/ACO-1 is involved in this elegans, the and of the glyoxylate cycle protein are and are in and in Biol. Scholar, 1997; 36: Scholar, J.M. Biol. 1995; Scholar). the of GEI-22/ACO-1 in to and in and found in amounts of L. and A. is that GEI-22/ACO-1 activity these for GEI-22/ACO-1 are by that the of GEI-22/ACO-1 are not identical with glyoxylate cycle For example, glyoxylate cycle protein is expressed in and 1997; 36: Scholar, J.M. Biol. 1995; Scholar), whereas GEI-22/ACO-1 is expressed in cells and but not in a study that GEI-22/ACO-1 with in a D. K. M. K. Biochem. Res. Scholar). is to a is essential for and and in its cells to K. M. D. K. Scholar). The of GEI-22/ACO-1 to cells and its with a that GEI-22/ACO-1 have a function in development in by RNA D. K. M. K. Biochem. Res. Scholar). These that have other in cells or that can for To C. elegans iron the regulation of C. elegans ftn-1 and are conserved iron storage proteins found in plants, and animals that can up to iron by prevent iron toxicity P. 1996; Scholar, Blood. Scholar). are of H and L and whereas those of plants and bacteria H amino that are required for activity, whereas the in iron and iron In mammalian and are regulated the by the regulation of ferritin has been in mammalian cells K. J. Biol. Chem. Scholar), but this plays a role in iron GEI-22/ACO-1 not bind and C. elegans lacks IREs, we that ftn-1 mRNAs regulated by iron processes other that ftn-1 mRNA increased in in the presence of iron, mRNA a but consistent In contrast, decreased ftn-1 mRNAs and for the in ftn-1 mRNA by iron is that are in medium and coli and are The also show mRNA is to iron concentration mRNA. in A. where the and are to iron J.M. S. Biochem. J. 2001; Scholar), and in where but is K. S. M. Eur. J. Biochem. 1995; Scholar, S. J. Biol. Chem. 1997; Scholar, J.M. S. J. Biol. Chem. 2001; Scholar). Although not show that ftn-1 and ftn-2 genes are regulated by iron in this mechanism consistent with the regulation of ferritin in plants J.M. S. Biochem. J. 2001; Scholar, J.M. S. J. Biol. Chem. 2001; Scholar, J. E.C. J. Biol. Chem. 2000; 275: Scholar) and in Winzerling J.J. Annu. Rev. Scholar). The of C. elegans to as and D. A. J. Biol. Chem. 1993; Scholar, A. B. R. M. EMBO J. 1996; 15: Scholar, J. Biol. Chem. 1998; Scholar, M. R. L. Y. EMBO J. 2000; Scholar, D. D.A. J. 2001; 3: Scholar, A. J. A. EMBO J. 2001; 20: Scholar), has been but is known iron regulation and toxicity in to the of iron on the development of in the of development of on of iron, did the life of The life of on and and with on Although the mechanism for in life is not it is that on high iron iron as leading to increased free in the of free radicals the leading to cellular damage and show that free radicals are decreased S. J. S. D.W. B. 2000; Scholar, J. S. 2001; Scholar) or as and are increased A. D. Phillips 1998; Scholar, J. C. R. J. M. 1999; Scholar, J. J. Mol. Biol. 1999; Scholar), the life of the organism can The toxicity of iron in to iron in humans, where the accumulation of iron a can result in cirrhosis, cardiomyopathy, diabetes mellitus, and increased risk of cancer Annu. Rev. Physiol. Scholar). These studies show that C. elegans serve as a for the study of iron homeostasis in and and for on worm and for and for of the and for with the C. elegans for and and the of DNA for the of Cell for in worm and the for