title: Haemolysis and perturbations in the systemic iron metabolism of suckling, copper-deficient mosaic mutant mice - an animal model of Menkes disease.
abstract: The biological interaction between copper and iron is best exemplified by the decreased activity of multicopper ferroxidases under conditions of copper deficiency that limits the availability of iron for erythropoiesis. However, little is known about how copper deficiency affects iron homeostasis through alteration of the activity of other copper-containing proteins, not directly connected with iron metabolism, such as superoxide dismutase 1 (SOD1). This antioxidant enzyme scavenges the superoxide anion, a reactive oxygen species contributing to the toxicity of iron via the Fenton reaction. Here, we analyzed changes in the systemic iron metabolism using an animal model of Menkes disease: copper-deficient mosaic mutant mice with dysfunction of the ATP7A copper transporter. We found that the erythrocytes of these mutants are copper-deficient, display decreased SOD1 activity/expression and have cell membrane abnormalities. In consequence, the mosaic mice show evidence of haemolysis accompanied by haptoglobin-dependent elimination of haemoglobin (Hb) from the circulation, as well as the induction of haem oxygenase 1 (HO1) in the liver and kidney. Moreover, the hepcidin-ferroportin regulatory axis is strongly affected in mosaic mice. These findings indicate that haemolysis is an additional pathogenic factor in a mouse model of Menkes diseases and provides evidence of a new indirect connection between copper deficiency and iron metabolism.
authors.affiliation: Department of Genetics and Evolution, Institute of Zoology, Jagiellonian University, Kraków, Poland.
authors.forename: Małgorzata
authors.initials: M
authors.lastname: Lenartowicz
authors.affiliation: Department of Molecular Biology, Institute of Genetics and Animal Breeding, Polish Academy of Sciences, Magdalenka, Poland.
authors.forename: Rafał R
authors.initials: RR
authors.lastname: Starzyński
authors.affiliation: Department of Cell Biology and Imaging, Institute of Zoology, Jagiellonian University, Kraków, Poland.
authors.forename: Wojciech
authors.initials: W
authors.lastname: Krzeptowski
authors.affiliation: Department of Genetics and Evolution, Institute of Zoology, Jagiellonian University, Kraków, Poland.
authors.forename: Paweł
authors.initials: P
authors.lastname: Grzmil
authors.affiliation: Department of Genetics and Evolution, Institute of Zoology, Jagiellonian University, Kraków, Poland.
authors.forename: Aleksandra
authors.initials: A
authors.lastname: Bednarz
authors.affiliation: Department of Genetics and Evolution, Institute of Zoology, Jagiellonian University, Kraków, Poland.
authors.forename: Mateusz
authors.initials: M
authors.lastname: Ogórek
authors.affiliation: Department of Genetics and Evolution, Institute of Zoology, Jagiellonian University, Kraków, Poland.
authors.forename: Olga
authors.initials: O
authors.lastname: Pierzchała
authors.affiliation: Department of Molecular Biology, Institute of Genetics and Animal Breeding, Polish Academy of Sciences, Magdalenka, Poland.
authors.forename: Robert
authors.initials: R
authors.lastname: Staroń
authors.affiliation: Department of Molecular Biology, Institute of Genetics and Animal Breeding, Polish Academy of Sciences, Magdalenka, Poland.
authors.forename: Anna
authors.initials: A
authors.lastname: Gajowiak
authors.affiliation: Department of Molecular Biology, Institute of Genetics and Animal Breeding, Polish Academy of Sciences, Magdalenka, Poland.
authors.forename: Paweł
authors.initials: P
authors.lastname: Lipiński
mesh_terms: D000251:Adenosine Triphosphatases / Q000235:genetics* / Q000378:metabolism*; D000818:Animals; D027682:Cation Transport Proteins / Q000235:genetics* / Q000378:metabolism*; D002460:Cell Line; D003300:Copper / Q000378:metabolism*; D000073840:Copper-Transporting ATPases; D004195:Disease Models, Animal; D004912:Erythrocytes / Q000378:metabolism / Q000473:pathology; D005260:Female; D005786:Gene Expression Regulation; D051547:Heme Oxygenase-1 / Q000235:genetics / Q000378:metabolism; D006461:Hemolysis; D064451:Hepcidins / Q000235:genetics / Q000378:metabolism; D006801:Humans; D007501:Iron / Q000378:metabolism*; D007668:Kidney / Q000378:metabolism; D008099:Liver / Q000378:metabolism; D008297:Male; D008565:Membrane Proteins / Q000235:genetics / Q000378:metabolism; D007706:Menkes Kinky Hair Syndrome / Q000097:blood / Q000235:genetics / Q000473:pathology*; D051379:Mice; D009154:Mutation; D013482:Superoxide Dismutase / Q000235:genetics / Q000378:metabolism; D000072105:Superoxide Dismutase-1; D000098742:Ferroportin
chemical_list: C486201:Atp7a protein, mouse; D027682:Cation Transport Proteins; D064451:Hepcidins; D008565:Membrane Proteins; C000606290:SOD1 protein, human; D000098742:Ferroportin; D003300:Copper; D007501:Iron; D051547:Heme Oxygenase-1; C496542:Hmox1 protein, mouse; C000606291:Sod1 protein, mouse; D013482:Superoxide Dismutase; D000072105:Superoxide Dismutase-1; D000251:Adenosine Triphosphatases; D000073840:Copper-Transporting ATPases