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FASEB J. 2019 Feb;33(2):2228-2240. doi: 10.1096/fj.201800831R. Epub 2018 Sep 24.

Ferroportin disease mutations influence manganese accumulation and cytotoxicity.

Author information

1
Department of Nutritional Sciences, University of Michigan School of Public Health, Ann Arbor, Michigan, USA; and.
2
Department of Human Genetics, University of Michigan, Ann Arbor, Michigan, USA.

Abstract

Hemochromatosis is a frequent genetic disorder, characterized by the accumulation of excess iron across tissues. Mutations in the FPN1 gene, encoding a cell surface iron exporter [ferroportin (Fpn)], are responsible for hemochromatosis type 4, also known as ferroportin disease. Recently, Fpn has been implicated in the regulation of manganese (Mn), another essential nutrient required for numerous cellular enzymes. However, the roles of Fpn in Mn regulation remain ill-defined, and the impact of disease mutations on cellular Mn levels is unknown. Here, we provide evidence that Fpn can export Mn from cells into extracellular space. Fpn seems to play protective roles in Mn-induced cellular toxicity and oxidative stress. Finally, disease mutations interfere with the role of Fpn in controlling Mn levels as well as the stability of Fpn. These results define the function of Fpn as an exporter of both iron and Mn and highlight the potential involvement of Mn dysregulation in ferroportin disease.-Choi, E.-K., Nguyen, T.-T., Iwase, S., Seo, Y. A. Ferroportin disease mutations influence manganese accumulation and cytotoxicity.

KEYWORDS:

iron metabolism; manganese toxicity; manganese transport

PMID:
30247984
PMCID:
PMC6338638
DOI:
10.1096/fj.201800831R

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