Haemolysis and perturbations in the systemic iron metabolism of suckling, copper-deficient mosaic mutant mice - an animal model of Menkes disease

Małgorzata Lenartowicz; Rafał R Starzyński; Wojciech Krzeptowski; Paweł Grzmil; Aleksandra Bednarz; Mateusz Ogórek; Olga Pierzchała; Robert Staroń; Anna Gajowiak; Paweł Lipiński

doi:10.1371/journal.pone.0107641

Haemolysis and perturbations in the systemic iron metabolism of suckling, copper-deficient mosaic mutant mice - an animal model of Menkes disease

PLoS One. 2014 Sep 23;9(9):e107641. doi: 10.1371/journal.pone.0107641. eCollection 2014.

Affiliations

¹ Department of Genetics and Evolution, Institute of Zoology, Jagiellonian University, Kraków, Poland.
² Department of Molecular Biology, Institute of Genetics and Animal Breeding, Polish Academy of Sciences, Magdalenka, Poland.
³ Department of Cell Biology and Imaging, Institute of Zoology, Jagiellonian University, Kraków, Poland.

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.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Adenosine Triphosphatases / genetics*
Adenosine Triphosphatases / metabolism*
Animals
Cation Transport Proteins / genetics*
Cation Transport Proteins / metabolism*
Cell Line
Copper / metabolism*
Copper-Transporting ATPases
Disease Models, Animal
Erythrocytes / metabolism
Erythrocytes / pathology
Female
Gene Expression Regulation
Heme Oxygenase-1 / genetics
Heme Oxygenase-1 / metabolism
Hemolysis*
Hepcidins / genetics
Hepcidins / metabolism
Humans
Iron / metabolism*
Kidney / metabolism
Liver / metabolism
Male
Membrane Proteins / genetics
Membrane Proteins / metabolism
Menkes Kinky Hair Syndrome / blood
Menkes Kinky Hair Syndrome / genetics
Menkes Kinky Hair Syndrome / pathology*
Mice
Mutation
Superoxide Dismutase / genetics
Superoxide Dismutase / metabolism
Superoxide Dismutase-1

Substances

Atp7a protein, mouse
Cation Transport Proteins
Hepcidins
Membrane Proteins
SOD1 protein, human
metal transporting protein 1
Copper
Iron
Heme Oxygenase-1
Hmox1 protein, mouse
Sod1 protein, mouse
Superoxide Dismutase
Superoxide Dismutase-1
Adenosine Triphosphatases
Copper-Transporting ATPases

Grants and funding

This work was supported by grant no. K/PBO/000142 from the National Science Center of Poland. This work was supported by The National Science Centre grant 2012/05/B/NZ4/02423 and partially by funding from the Jagiellonian University within the SET project, which is cofinanced by the European Union. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.