title: Ferroportin is a manganese-responsive protein that decreases manganese cytotoxicity and accumulation.
abstract: Although manganese (Mn) is an essential trace element for human development and growth, chronic exposure to excessive Mn levels can result in psychiatric and motor disturbances, referred to as manganism. However, there are no known mechanism(s) for efflux of excess Mn from mammalian cells. Here, we test the hypothesis that the cytoplasmic iron (Fe) exporter ferroportin (Fpn) may also function as a Mn exporter to attenuate Mn toxicity. Using an inducible human embryonic kidney (HEK293T) cell model, we examined the influence of Fpn expression on Mn-induced cytotoxicity and intracellular Mn concentrations. We found that induction of an Fpn-green fluorescent protein fusion protein in HEK293T cells was cytoprotective against several measures of Mn toxicity, including Mn-induced cell membrane leakage and Mn-induced reductions in glutamate uptake. Fpn-green fluorescent protein mediated cytoprotection correlated with decreased Mn accumulation following Mn exposure. Thus, Fpn expression reduces Mn toxicity concomitant with reduced Mn accumulation. To determine if mammalian cells may utilize Fpn in response to increased intracellular Mn concentrations and toxicity, we assessed endogenous Fpn levels in Mn-exposed HEK293T cells and in mouse brain in vivo. We find that 6 h of Mn exposure in HEK293T cells is associated with a significant increase in Fpn levels. Furthermore, mice exposed to Mn showed an increase in Fpn levels in both the cerebellum and cortex. Collectively, these results indicate that (i) Mn exposure promotes Fpn protein expression, (ii) Fpn expression reduces net Mn accumulation, and (iii) reduces cytotoxicity associated with exposure to this metal.
authors.affiliation: Departments of Pediatrics and Pharmacology, and Kennedy Center for Research on Human Development, Vanderbilt University Medical Center, Nashville, TN 37232, USA.
authors.forename: Zhaobao
authors.initials: Z
authors.lastname: Yin
authors.forename: Haiyan
authors.initials: H
authors.lastname: Jiang
authors.forename: Eun-Sook Y
authors.initials: ES
authors.lastname: Lee
authors.forename: Mingwei
authors.initials: M
authors.lastname: Ni
authors.forename: Keith M
authors.initials: KM
authors.lastname: Erikson
authors.forename: Dejan
authors.initials: D
authors.lastname: Milatovic
authors.forename: Aaron B
authors.initials: AB
authors.lastname: Bowman
authors.forename: Michael
authors.initials: M
authors.lastname: Aschner
mesh_terms: D000704:Analysis of Variance; D000818:Animals; D027682:Cation Transport Proteins / Q000235:genetics / Q000378:metabolism* / Q000627:therapeutic use*; D002461:Cell Line, Transformed; D002531:Cerebellum / Q000187:drug effects / Q000378:metabolism; D002540:Cerebral Cortex / Q000187:drug effects / Q000378:metabolism; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D004441:Ecdysterone / Q000031:analogs & derivatives / Q000494:pharmacology; D005260:Female; D005786:Gene Expression Regulation / Q000187:drug effects; D018698:Glutamic Acid / Q000378:metabolism; D049452:Green Fluorescent Proteins / Q000235:genetics; D006801:Humans; D042541:Intracellular Space / Q000187:drug effects / Q000378:metabolism; D008345:Manganese / Q000633:toxicity*; D020149:Manganese Poisoning / Q000188:drug therapy* / Q000209:etiology / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D014162:Transfection; D000098742:Ferroportin
chemical_list: D027682:Cation Transport Proteins; D000098742:Ferroportin; D049452:Green Fluorescent Proteins; D018698:Glutamic Acid; D008345:Manganese; D004441:Ecdysterone; C008999:ponasterone A