Ferroportin disease mutations influence manganese accumulation and cytotoxicity

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. FASEB J. 33, 2228–2240 (2019). http://www.fasebj.org

Manganese transporter Slc30a10 controls physiological manganese excretion and toxicity

“…With consideration of these findings, our view of the molecular basis of Mn homeostasis is as follows: Mn is absorbed through the intestinal epithelium, however the essential factors have not been identified. The iron transporters SLC11A2 and SLC40A1 may contribute to this absorption process, however data supporting a critical role are lacking (7)(8)(9)(10)(11)(12)14). In intestinal enterocytes, SLC39A14 at the basolateral membrane and SLC30A10 at the apical membrane limit Mn absorption and/or enhance intestinal Mn excretion (15,16).…”

“…Dietary Mn may be absorbed into duodenal enterocytes by SLC11A2 (also known as divalent metal transporter 1 [DMT1]), however, in vivo data suggest that SLC11A2 is not necessary for Mn absorption (6,7). Mn may be exported from enterocytes into blood by the iron transporter SLC40A1 (ferroportin), however, evidence for the role of SLC40A1 in Mn homeostasis remains controversial (8)(9)(10)(11)(12)(13)(14). The metal importer SLC39A14 (also known as ZIP14) and exporter SLC30A10 (also known as ZNT10) have been implicated in Mn transport across the intestines.…”

Impact of dietary manganese on experimental colitis in mice

“…The actual Mn concentrations of the diets were 0-0.5 ppm Mn (Mn-deficient), 35-35.5 ppm Mn (Mn-adequate), and 300-301 ppm Mn (Mn-supplemented), as determined previously by inductively coupled plasma mass spectrometry (ICP-MS). 13,14 For colitis induction, mice were provided with water containing 3% (w/v) DSS for 6 days (inflammatory phase). The mice were then placed on regular drinking water for 7 days (recovery phase).…”

ZIP14 is degraded in response to manganese exposure

“…A prevalent view is that the liver is the organ responsible for the clearance of ingested Mn through the first-pass-hepatic clearance system, although increasing evidence supports a crucial role for the intestine in the regulation of circulating levels (Scheiber et al 2019;Taylor et al 2019). A number of recent genetic studies have determined that disruptions in Mn acquisition, accumulation and deposition result from defects in human genes thought to be involved Mn transport and homeostasis, including SLC39A14 (ZIP14), SLC39A8 (ZIP8), and SLC30A10 (ZNT10) (Aydemir et al 2017;Boycott et al 2015;Choi et al 2019;Hutchens et al 2017;Jenkitkasemwong et al 2018;Lin et al 2017;Liu et al 2017;Marti-Sanchez et al 2018;Park et al 2015;Quadri et al 2012Quadri et al , 2015Riley et al 2017;Xin et al 2017). In particular, human mutations in ZIP14 lead to hypermanganesemia and neurological disorders.…”

“…Mn has been shown to be toxic to a variety of cell types at lM concentrations (Choi et al 2019;Fernandes et al 2019;Porte Alcon et al 2018;Roth et al 2002).…”