Ferroportin is a manganese-responsive protein that decreases manganese cytotoxicity and accumulation

Zhaobao Yin, Haiyan Jiang, Eun Sook Y Lee, Mingwei Ni, Keith M. Erikson, Dejan Milatovic, Aaron B. Bowman, Michael Aschner

Research output: Contribution to journalArticle

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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.

Original languageEnglish (US)
Pages (from-to)1190-1198
Number of pages9
JournalJournal of Neurochemistry
Volume112
Issue number5
DOIs
StatePublished - Mar 2010
Externally publishedYes

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Cytotoxicity
Manganese
Proteins
Toxicity
metal transporting protein 1
Green Fluorescent Proteins
Cells
Cytoprotection
Trace Elements
Human Development
Cell membranes

Keywords

  • Cytotoxicity
  • Divalent metal transporter
  • Exporter
  • Ferroportin
  • Iron
  • Manganese

ASJC Scopus subject areas

  • Biochemistry
  • Cellular and Molecular Neuroscience

Cite this

Ferroportin is a manganese-responsive protein that decreases manganese cytotoxicity and accumulation. / Yin, Zhaobao; Jiang, Haiyan; Lee, Eun Sook Y; Ni, Mingwei; Erikson, Keith M.; Milatovic, Dejan; Bowman, Aaron B.; Aschner, Michael.

In: Journal of Neurochemistry, Vol. 112, No. 5, 03.2010, p. 1190-1198.

Research output: Contribution to journalArticle

Yin, Zhaobao ; Jiang, Haiyan ; Lee, Eun Sook Y ; Ni, Mingwei ; Erikson, Keith M. ; Milatovic, Dejan ; Bowman, Aaron B. ; Aschner, Michael. / Ferroportin is a manganese-responsive protein that decreases manganese cytotoxicity and accumulation. In: Journal of Neurochemistry. 2010 ; Vol. 112, No. 5. pp. 1190-1198.
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