Down-regulation of iron regulatory protein 1 activities and expression in superoxide dismutase 1 knock-out mice is not associated with alterations in iron metabolism.
Iron and oxygen (O2) are intimately associated in many well characterized patho-physiological processes. These include oxidation of the [4Fe-4S] cluster of mitochondrial aconitase and inactivation of this Krebs cycle enzyme by the superoxide anion (O2*-), a product of the one-electron of reduction O2. In contrast to the apparent toxicity of this reaction, the biological consequences of O2*- -mediated inactivation of the cytosolic counterpart of mitochondrial aconitase, commonly known as iron regulatory protein 1 (IRP1), are not clear. Apart from its ability to convert citrate to iso-citrate, IRP1 in its apo-form binds to iron-responsive elements in the untranslated regions of mRNAs coding for proteins involved in iron metabolism, to regulate their synthesis and thus control the cellular homeostasis of this metal. Here, we show that in superoxide dismutase 1 (SOD1) knock-out mice, lacking Cu,Zn-SOD, an enzyme that acts to reduce the concentration of O2*- mainly in cytosol, not only is aconitase activity of IRP1 inhibited but the level of IRP1 is also strongly decreased. Despite such an evident alteration in IRP1 status, SOD1-deficient mice display a normal iron metabolism phenotype. Our findings clearly show that under conditions of O2*- -mediated oxidative stress, IRP1 is not essential for the maintenance of iron metabolism in mammals.
Starzynski
Rafal R
RR
Department of Molecular Biology, Institute of Genetics and Animal Breeding, Polish Academy of Sciences, Jastrzêbiec, 05-552 Wólka Kosowska, Poland.
Lipinski
Pawel
P
Drapier
Jean-Claude
JC
Diet
Alexandre
A
Smuda
Ewa
E
Bartlomiejczyk
Teresa
T
Gralak
Mikolaj A
MA
Kruszewski
Marcin
M
D000154:Aconitate Hydratase / Q000378:metabolism; D000483:Alleles; D000818:Animals; D015153:Blotting, Western; D019343:Citric Acid / Q000737:chemistry; D003600:Cytosol / Q000378:metabolism; D017931:DNA Primers / Q000737:chemistry; D015536:Down-Regulation; D005609:Free Radicals; D005838:Genotype; D006418:Heme / Q000737:chemistry; D006579:Heterozygote; D007501:Iron / Q000378:metabolism*; D035941:Iron Regulatory Protein 1 / Q000096:biosynthesis* / Q000235:genetics / Q000502:physiology; D007523:Isocitrates / Q000737:chemistry; D008099:Liver / Q000378:metabolism; D051379:Mice; D018345:Mice, Knockout; D008822:Mice, Transgenic; D018384:Oxidative Stress; D010100:Oxygen / Q000378:metabolism; D010641:Phenotype; D020033:Protein Isoforms; D012333:RNA, Messenger / Q000378:metabolism; D011990:Receptors, Transferrin / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013482:Superoxide Dismutase / Q000235:genetics*; D000072105:Superoxide Dismutase-1
D017931:DNA Primers; D005609:Free Radicals; D007523:Isocitrates; D020033:Protein Isoforms; D012333:RNA, Messenger; D011990:Receptors, Transferrin; D019343:Citric Acid; D006418:Heme; C034219:isocitric acid; D007501:Iron; C000606291:Sod1 protein, mouse; D013482:Superoxide Dismutase; D000072105:Superoxide Dismutase-1; D000154:Aconitate Hydratase; D035941:Iron Regulatory Protein 1; D010100:Oxygen