Department of Nutritional Sciences, University of Michigan School of Public Health, Ann Arbor, Michigan, USA; and.
Department of Human Genetics, University of Michigan, Ann Arbor, Michigan, USA.
FASEB J. 2019 Feb;33(2):2228-2240. doi: 10.1096/fj.201800831R. Epub 2018 Sep 24.
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.
血色病是一种常见的遗传性疾病，其特征是组织中铁元素积累过多。编码细胞表面铁输出蛋白[铁蛋白（Fpn）]的 FPN1 基因突变导致 4 型血色病，也称为铁蛋白病。最近，Fpn 被认为参与了锰（Mn）的调节，Mn 是许多细胞酶所需的另一种必需营养物质。然而，Fpn 在 Mn 调节中的作用仍不明确，疾病突变对细胞 Mn 水平的影响尚不清楚。在这里，我们提供了证据表明 Fpn 可以将 Mn 从细胞内运出到细胞外空间。Fpn 似乎在 Mn 诱导的细胞毒性和氧化应激中发挥保护作用。最后，疾病突变干扰了 Fpn 控制 Mn 水平以及 Fpn 稳定性的作用。这些结果将 Fpn 的功能定义为铁和 Mn 的输出蛋白，并强调了 Mn 失调在铁蛋白病中的潜在作用。
