The role of multicopper ferroxidases in mammalian iron homeostasis (995.2)

Abstract

Introduction: Multicopper ferroxidases (MCFs) are proteins important for intestinal iron absorption and iron recycling. MCFs are hypothesized to oxidize ferrous iron from the iron exporter Ferroportin so that the iron can bind to circulating Transferrin. There are three known MCFs expressed in vertebrates: Ceruloplasmin (CP), Hephaestin (HP), and the recently discovered Zyklopen (ZP). In order to determine the individual and overlapping roles of the MCFs, we generated mouse models with single, double, and triple MCF knockout. Methods: We used the cre‐lox system to create HP and ZP knockouts and then crossed these mice with each other and with CP knockout mice to generate double and triple knockouts. The general phenotype, hematology, tissue iron levels, and the absorption and distribution of radiolabeled iron were then studied. Results: Mice lacking HP and/or CP exhibited clear defects in iron metabolism, with double knockout leading to a severe anemia and fatality at 23‐30 weeks of age. Mice with knockout of ZP appeared grossly normal except for hair abnormalities including curly whiskers. The phenotypes of double knockout mice lacking ZP and CP or HP were not grossly different than what would be expected from the simple combination of the single knockout phenotypes. Triple MCF knockout mice were viable and able to absorb dietary iron but were severely anemic. Conclusions: Our findings indicate that MCFs are not absolutely required for iron absorption and survival into adulthood. The severity of the phenotype of HP CP double knockout mice indicates that these proteins are particularly important in iron metabolism, while the phenotype of the ZP knockout mice suggests a role for ZP in copper metabolism.