title: Ferroportin deficiency impairs manganese metabolism in flatiron mice.
abstract: We examined the physiologic role of ferroportin (Fpn) in manganese (Mn) export using flatiron (ffe/+) mice, a genetic model of Fpn deficiency. Blood (0.0123 vs. 0.0107 mg/kg; P = 0.0003), hepatic (1.06 vs. 0.96 mg/kg; P = 0.0125), and bile Mn levels (79 vs. 38 mg/kg; P = 0.0204) were reduced in ffe/+ mice compared to +/+ controls. Erythrocyte Mn-superoxide dismutase was also reduced at 6 (0.154 vs. 0.096, P = 0.0101), 9 (0.131 vs. 0.089, P = 0.0162), and 16 weeks of age (0.170 vs. 0.090 units/mg protein/min; P < 0.0001). (54)Mn uptake after intragastric gavage was markedly reduced in ffe/+ mice (0.0187 vs. 0.0066% dose; P = 0.0243), while clearance of injected isotope was similar in ffe/+ and +/+ mice. These values were compared to intestinal absorption of (59)Fe, which was significantly reduced in ffe/+ mice (8.751 vs. 3.978% dose; P = 0.0458). The influence of the ffe mutation was examined in dopaminergic SH-SY5Y cells and human embryonic HEK293T cells. While expression of wild-type Fpn reversed Mn-induced cytotoxicity, ffe mutant H32R failed to confer protection. These combined results demonstrate that Fpn plays a central role in Mn transport and that flatiron mice provide an excellent genetic model to explore the role of this exporter in Mn homeostasis. -
authors.affiliation: Departments of Genetics and Complex Diseases and Nutrition, Harvard School of Public Health, Boston, Massachusetts, USA.
authors.forename: Young Ah
authors.initials: YA
authors.lastname: Seo
authors.affiliation: Departments of Genetics and Complex Diseases and Nutrition, Harvard School of Public Health, Boston, Massachusetts, USA wessling@hsph.harvard.edu.
authors.forename: Marianne
authors.initials: M
authors.lastname: Wessling-Resnick
mesh_terms: D000818:Animals; D001693:Biological Transport, Active; D027682:Cation Transport Proteins / Q000172:deficiency* / Q000235:genetics / Q000378:metabolism; D002460:Cell Line; D059290:Dopaminergic Neurons / Q000187:drug effects / Q000378:metabolism; D057809:HEK293 Cells; D006706:Homeostasis; D006801:Humans; D007408:Intestinal Absorption; D007501:Iron / Q000378:metabolism; D000090463:Iron Deficiencies; D008345:Manganese / Q000378:metabolism* / Q000633:toxicity; D051379:Mice; D008817:Mice, Mutant Strains; D023421:Models, Animal; D008957:Models, Genetic; D020125:Mutation, Missense; D009498:Neurotoxins / Q000378:metabolism / Q000633:toxicity; D000098742:Ferroportin
chemical_list: D027682:Cation Transport Proteins; D009498:Neurotoxins; D000098742:Ferroportin; D008345:Manganese; D007501:Iron
keywords: hepcidin; iron metabolism; manganese transport