Functional properties of mouse ferroportin, a cellular iron‐export protein

Abstract

Iron homeostasis is a topic of great public‐health importance because of the high prevalence of iron‐deficiency anemia and of hereditary disorders that cause iron overload. Ferroportin (Fpn)—the only known mammalian cellular iron exporter—is expressed on the plasma membrane of macrophages, enterocytes, and hepatocytes. Fpn, under the control of the iron‐regulatory hormone hepcidin, serves a critical role in the regulation of systemic iron. Whereas we have previously characterized the functional properties of human Fpn, a great deal of research in iron homeostasis utilizes mouse models, highlighting the need to study mouse Fpn in vitro. For example, the flatiron mouse model of classical ferroportin disease bears the mutation H32R in mFpn and is characterized by systemic iron deficiency and macrophage iron loading. The flatiron mouse also appears to exhibit a manganese phenotype [Seo YA and Wessling‐Resnick M (2015) FASEB J 28, 2726–2733], raising the possibility that mouse Fpn (mFpn) serves a role in Mn metabolism, although Mn is not a substrate of human Fpn. We therefore tested the hypothesis that mouse but not human Fpn can transport Mn. We characterized the functional properties of mFpn by using radiotracer assays in RNA‐injected Xenopus oocytes expressing mouse or human Fpn. We found that mFpn can export several transition metals, with selectivity Fe > Co > Ni, but not Cd. Whereas the H32R mutant abolished mFpn‐mediated Fe efflux relative to wildtype, neither wildtype nor mutant mFpn could transport Mn. mFpn‐mediated Fe efflux was pH‐dependent with estimated optimal pH of 8.2 ± (SEM) 0.2 when [Ca2+]o = 2 mM. mFpn‐mediated Fe efflux was activated by extracellular Ca2+, proceeded independently of extracellular Na+, and was inhibited 51% ± 1% by 10 μM hepcidin (30‐min preincubation). Our data (i) reveal that human and mouse Fpn share similar functional properties and (ii) do not support the notion that Fpn can transport Mn.Support or Funding InformationNIH grants R01 DK107309, P30 DK078392, and R25 HL115473, and the American Physiological SocietyThis abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.