Logo of pnasPNASInfo for AuthorsSubscriptionsAboutThis Article
Proc Natl Acad Sci U S A. 1996 May 14; 93(10): 4925–4930.

Translational regulation of mammalian and Drosophila citric acid cycle enzymes via iron-responsive elements.


The posttranscriptional control of iron uptake, storage, and utilization by iron-responsive elements (IREs) and iron regulatory proteins (IRPs) provides a molecular framework for the regulation of iron homeostasis in many animals. We have identified and characterized IREs in the mRNAs for two different mitochondrial citric acid cycle enzymes. Drosophila melanogaster IRP binds to an IRE in the 5' untranslated region of the mRNA encoding the iron-sulfur protein (Ip) subunit of succinate dehydrogenase (SDH). This interaction is developmentally regulated during Drosophila embryogenesis. In a cell-free translation system, recombinant IRP-1 imposes highly specific translational repression on a reporter mRNA bearing the SDH IRE, and the translation of SDH-Ip mRNA is iron regulated in D. melanogaster Schneider cells. In mammals, an IRE was identified in the 5' untranslated regions of mitochondrial aconitase mRNAs from two species. Recombinant IRP-1 represses aconitase synthesis with similar efficiency as ferritin IRE-controlled translation. The interaction between mammalian IRPs and the aconitase IRE is regulated by iron, nitric oxide, and oxidative stress (H2O2), indicating that these three signals can control the expression of mitochondrial aconitase mRNA. Our results identify a regulatory link between energy and iron metabolism in vertebrates and invertebrates, and suggest biological functions for the IRE/IRP regulatory system in addition to the maintenance of iron homeostasis.

Full text

Full text is available as a scanned copy of the original print version. Get a printable copy (PDF file) of the complete article (2.0M), or click on a page image below to browse page by page. Links to PubMed are also available for Selected References.

Images in this article

Click on the image to see a larger version.

Selected References

These references are in PubMed. This may not be the complete list of references from this article.
  • Melefors O, Hentze MW. Translational regulation by mRNA/protein interactions in eukaryotic cells: ferritin and beyond. Bioessays. 1993 Feb;15(2):85–90. [PubMed]
  • Klausner RD, Rouault TA, Harford JB. Regulating the fate of mRNA: the control of cellular iron metabolism. Cell. 1993 Jan 15;72(1):19–28. [PubMed]
  • Guo B, Yu Y, Leibold EA. Iron regulates cytoplasmic levels of a novel iron-responsive element-binding protein without aconitase activity. J Biol Chem. 1994 Sep 30;269(39):24252–24260. [PubMed]
  • DeRusso PA, Philpott CC, Iwai K, Mostowski HS, Klausner RD, Rouault TA. Expression of a constitutive mutant of iron regulatory protein 1 abolishes iron homeostasis in mammalian cells. J Biol Chem. 1995 Jun 30;270(26):15451–15454. [PubMed]
  • Swenson GR, Patino MM, Beck MM, Gaffield L, Walden WE. Characteristics of the interaction of the ferritin repressor protein with the iron-responsive element. Biol Met. 1991;4(1):48–55. [PubMed]
  • Walden WE, Patino MM, Gaffield L. Purification of a specific repressor of ferritin mRNA translation from rabbit liver. J Biol Chem. 1989 Aug 15;264(23):13765–13769. [PubMed]
  • Melefors O, Goossen B, Johansson HE, Stripecke R, Gray NK, Hentze MW. Translational control of 5-aminolevulinate synthase mRNA by iron-responsive elements in erythroid cells. J Biol Chem. 1993 Mar 15;268(8):5974–5978. [PubMed]
  • Gray NK, Quick S, Goossen B, Constable A, Hirling H, Kühn LC, Hentze MW. Recombinant iron-regulatory factor functions as an iron-responsive-element-binding protein, a translational repressor and an aconitase. A functional assay for translational repression and direct demonstration of the iron switch. Eur J Biochem. 1993 Dec 1;218(2):657–667. [PubMed]
  • Gray NK, Hentze MW. Iron regulatory protein prevents binding of the 43S translation pre-initiation complex to ferritin and eALAS mRNAs. EMBO J. 1994 Aug 15;13(16):3882–3891. [PMC free article] [PubMed]
  • Binder R, Horowitz JA, Basilion JP, Koeller DM, Klausner RD, Harford JB. Evidence that the pathway of transferrin receptor mRNA degradation involves an endonucleolytic cleavage within the 3' UTR and does not involve poly(A) tail shortening. EMBO J. 1994 Apr 15;13(8):1969–1980. [PMC free article] [PubMed]
  • Casey JL, Hentze MW, Koeller DM, Caughman SW, Rouault TA, Klausner RD, Harford JB. Iron-responsive elements: regulatory RNA sequences that control mRNA levels and translation. Science. 1988 May 13;240(4854):924–928. [PubMed]
  • Müllner EW, Neupert B, Kühn LC. A specific mRNA binding factor regulates the iron-dependent stability of cytoplasmic transferrin receptor mRNA. Cell. 1989 Jul 28;58(2):373–382. [PubMed]
  • Henderson BR, Seiser C, Kühn LC. Characterization of a second RNA-binding protein in rodents with specificity for iron-responsive elements. J Biol Chem. 1993 Dec 25;268(36):27327–27334. [PubMed]
  • Rouault TA, Hentze MW, Caughman SW, Harford JB, Klausner RD. Binding of a cytosolic protein to the iron-responsive element of human ferritin messenger RNA. Science. 1988 Sep 2;241(4870):1207–1210. [PubMed]
  • Weiss G, Goossen B, Doppler W, Fuchs D, Pantopoulos K, Werner-Felmayer G, Wachter H, Hentze MW. Translational regulation via iron-responsive elements by the nitric oxide/NO-synthase pathway. EMBO J. 1993 Sep;12(9):3651–3657. [PMC free article] [PubMed]
  • Martins EA, Robalinho RL, Meneghini R. Oxidative stress induces activation of a cytosolic protein responsible for control of iron uptake. Arch Biochem Biophys. 1995 Jan 10;316(1):128–134. [PubMed]
  • Drapier JC, Hirling H, Wietzerbin J, Kaldy P, Kühn LC. Biosynthesis of nitric oxide activates iron regulatory factor in macrophages. EMBO J. 1993 Sep;12(9):3643–3649. [PMC free article] [PubMed]
  • Pantopoulos K, Hentze MW. Nitric oxide signaling to iron-regulatory protein: direct control of ferritin mRNA translation and transferrin receptor mRNA stability in transfected fibroblasts. Proc Natl Acad Sci U S A. 1995 Feb 28;92(5):1267–1271. [PMC free article] [PubMed]
  • Pantopoulos K, Hentze MW. Rapid responses to oxidative stress mediated by iron regulatory protein. EMBO J. 1995 Jun 15;14(12):2917–2924. [PMC free article] [PubMed]
  • Dandekar T, Stripecke R, Gray NK, Goossen B, Constable A, Johansson HE, Hentze MW. Identification of a novel iron-responsive element in murine and human erythroid delta-aminolevulinic acid synthase mRNA. EMBO J. 1991 Jul;10(7):1903–1909. [PMC free article] [PubMed]
  • Zheng L, Kennedy MC, Blondin GA, Beinert H, Zalkin H. Binding of cytosolic aconitase to the iron responsive element of porcine mitochondrial aconitase mRNA. Arch Biochem Biophys. 1992 Dec;299(2):356–360. [PubMed]
  • Stripecke R, Hentze MW. Bacteriophage and spliceosomal proteins function as position-dependent cis/trans repressors of mRNA translation in vitro. Nucleic Acids Res. 1992 Nov 11;20(21):5555–5564. [PMC free article] [PubMed]
  • Scherly D, Boelens W, van Venrooij WJ, Dathan NA, Hamm J, Mattaj IW. Identification of the RNA binding segment of human U1 A protein and definition of its binding site on U1 snRNA. EMBO J. 1989 Dec 20;8(13):4163–4170. [PMC free article] [PubMed]
  • Zheng L, Andrews PC, Hermodson MA, Dixon JE, Zalkin H. Cloning and structural characterization of porcine heart aconitase. J Biol Chem. 1990 Feb 15;265(5):2814–2821. [PubMed]
  • Leibold EA, Munro HN. Cytoplasmic protein binds in vitro to a highly conserved sequence in the 5' untranslated region of ferritin heavy- and light-subunit mRNAs. Proc Natl Acad Sci U S A. 1988 Apr;85(7):2171–2175. [PMC free article] [PubMed]
  • Dandekar T, Hentze MW. Finding the hairpin in the haystack: searching for RNA motifs. Trends Genet. 1995 Feb;11(2):45–50. [PubMed]
  • Hentze MW, Caughman SW, Casey JL, Koeller DM, Rouault TA, Harford JB, Klausner RD. A model for the structure and functions of iron-responsive elements. Gene. 1988 Dec 10;72(1-2):201–208. [PubMed]
  • Hentze MW, Rouault TA, Harford JB, Klausner RD. Oxidation-reduction and the molecular mechanism of a regulatory RNA-protein interaction. Science. 1989 Apr 21;244(4902):357–359. [PubMed]
  • Rothenberger S, Müllner EW, Kühn LC. The mRNA-binding protein which controls ferritin and transferrin receptor expression is conserved during evolution. Nucleic Acids Res. 1990 Mar 11;18(5):1175–1179. [PMC free article] [PubMed]
  • Haile DJ, Rouault TA, Tang CK, Chin J, Harford JB, Klausner RD. Reciprocal control of RNA-binding and aconitase activity in the regulation of the iron-responsive element binding protein: role of the iron-sulfur cluster. Proc Natl Acad Sci U S A. 1992 Aug 15;89(16):7536–7540. [PMC free article] [PubMed]
  • Constable A, Quick S, Gray NK, Hentze MW. Modulation of the RNA-binding activity of a regulatory protein by iron in vitro: switching between enzymatic and genetic function? Proc Natl Acad Sci U S A. 1992 May 15;89(10):4554–4558. [PMC free article] [PubMed]
  • Au HC, Scheffler IE. Characterization of the gene encoding the iron-sulfur protein subunit of succinate dehydrogenase from Drosophila melanogaster. Gene. 1994 Nov 18;149(2):261–265. [PubMed]
  • Goossen B, Caughman SW, Harford JB, Klausner RD, Hentze MW. Translational repression by a complex between the iron-responsive element of ferritin mRNA and its specific cytoplasmic binding protein is position-dependent in vivo. EMBO J. 1990 Dec;9(12):4127–4133. [PMC free article] [PubMed]
  • Goossen B, Hentze MW. Position is the critical determinant for function of iron-responsive elements as translational regulators. Mol Cell Biol. 1992 May;12(5):1959–1966. [PMC free article] [PubMed]
  • Dunkov BC, Zhang D, Choumarov K, Winzerling JJ, Law JH. Isolation and characterization of mosquito ferritin and cloning of a cDNA that encodes one subunit. Arch Insect Biochem Physiol. 1995;29(3):293–307. [PubMed]
  • Bhasker CR, Burgiel G, Neupert B, Emery-Goodman A, Kühn LC, May BK. The putative iron-responsive element in the human erythroid 5-aminolevulinate synthase mRNA mediates translational control. J Biol Chem. 1993 Jun 15;268(17):12699–12705. [PubMed]
  • Pantopoulos K, Gray NK, Hentze MW. Differential regulation of two related RNA-binding proteins, iron regulatory protein (IRP) and IRPB. RNA. 1995 Apr;1(2):155–163. [PMC free article] [PubMed]
  • Gardner PR, Nguyen DD, White CW. Aconitase is a sensitive and critical target of oxygen poisoning in cultured mammalian cells and in rat lungs. Proc Natl Acad Sci U S A. 1994 Dec 6;91(25):12248–12252. [PMC free article] [PubMed]
  • Hausladen A, Fridovich I. Superoxide and peroxynitrite inactivate aconitases, but nitric oxide does not. J Biol Chem. 1994 Nov 25;269(47):29405–29408. [PubMed]
  • Castro L, Rodriguez M, Radi R. Aconitase is readily inactivated by peroxynitrite, but not by its precursor, nitric oxide. J Biol Chem. 1994 Nov 25;269(47):29409–29415. [PubMed]

Articles from Proceedings of the National Academy of Sciences of the United States of America are provided here courtesy of National Academy of Sciences


Save items

Related citations in PubMed

See reviews...See all...

Cited by other articles in PMC

See all...


  • Compound
    PubChem chemical compound records that cite the current articles. These references are taken from those provided on submitted PubChem chemical substance records. Multiple substance records may contribute to the PubChem compound record.
  • Gene
    Gene records that cite the current articles. Citations in Gene are added manually by NCBI or imported from outside public resources.
  • GEO Profiles
    GEO Profiles
    Gene Expression Omnibus (GEO) Profiles of molecular abundance data. The current articles are references on the Gene record associated with the GEO profile.
  • HomoloGene
    HomoloGene clusters of homologous genes and sequences that cite the current articles. These are references on the Gene and sequence records in the HomoloGene entry.
  • MedGen
    Related information in MedGen
  • PubMed
    PubMed citations for these articles
  • Substance
    PubChem chemical substance records that cite the current articles. These references are taken from those provided on submitted PubChem chemical substance records.

Recent Activity

Your browsing activity is empty.

Activity recording is turned off.

Turn recording back on

See more...