Zip14 (Slc39a14) mediates non-transferrin-bound iron uptake into cells
Open accessAbstract
Zip14 is a member of the SLC39A zinc transporter family, which is involved in zinc uptake by cells. Up-regulation of Zip14 by IL-6 appears to contribute to the hepatic zinc accumulation and hypozincemia of inflammation. At least three members of the SLC39A family transport other trace elements, such as iron and manganese, in addition to zinc. We analyzed the capability of Zip14 to mediate non-transferrin-bound iron (NTBI) uptake by overexpressing mouse Zip14 in HEK 293H cells and Sf9 insect cells. Zip14 was found to localize to the plasma membrane, and its overexpression increased the uptake of both (65)Zn and (59)Fe. Addition of bathophenanthroline sulfonate, a cell-impermeant ferrous iron chelator, inhibited Zip14-mediated iron uptake from ferric citrate, suggesting that iron is taken up by HEK cells as Fe(2+). Iron uptake by HEK and Sf9 cells expressing Zip14 was inhibited by zinc. Suppression of endogenous Zip14 expression by using Zip14 siRNA reduced the uptake of both iron and zinc by AML12 mouse hepatocytes. Zip14 siRNA treatment also decreased metallothionein mRNA levels, suggesting that compensatory mechanisms were not sufficient to restore intracellular zinc. Collectively, these results indicate that Zip14 can mediate the uptake of zinc and NTBI into cells and that it may play a role in zinc and iron metabolism in hepatocytes, where this transporter is abundantly expressed. Because NTBI is commonly found in plasma of patients with hemochromatosis and transfusional iron overload, Zip14-mediated NTBI uptake may contribute to the hepatic iron loading that characterizes these diseases.
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Non-transferrin bound iron can be taken up into the cell by ZIP14 or DMT1.
“In the circulation there is also non-transferrin bound iron (NTBI) which can be taken up into the cell by ZIP- (ZRT/IRT-like protein)-14 or DMT1 (Ludwiczek et al., 2003; Liuzzi et al., 2006; Pinilla-Tenas et al., 2011; Figure 1);”
From The Role of Iron Regulation in Immunometabolism and Immune-Related Disease (2019) · cites this paper as Liuzzi et al., 2006
Knocking down frataxin with siRNA in human culture cells (HeLa and 293 cells) caused a defect in ISC proteins, including aconitase.
“Knocking down frataxin with siRNA in human culture cells (HeLa and 293 cells) caused a defect in ISC proteins, including aconitase (191, 281).”
From Intracellular iron transport and storage: from molecular mechanisms to health implications (2008) · cites this paper as [191]
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- Authors
- Liuzzi, J. P., Aydemir, F., Nam, H., Knutson, M. D., & Cousins, R. J.
- Affiliations
- University of Florida (US)
- Corresponding author
- Cousins, Robert J.
- Venue
- Proceedings of the National Academy of Sciences
- Publisher
- National Academy of Sciences
- Published
- 2006-09-12
- Volume
- 103
- Issue
- 37
- Pages
- 13612-13617
- ISSN
- 0027-8424 (ISSN-L)
- 1091-6490
- PMC
- PMC1564235
- OpenAlex
- W2047812782
- Cited by
- 577
- References
- 39
- Citations by year
- 2026: 29 · 2025: 19 · 2024: 33 · 2023: 22 · 2022: 42 · 2021: 38 · 2020: 41 · 2019: 34 · 2018: 32 · 2017: 36 · 2016: 21 · 2015: 32 · 2014: 29 · 2013: 25 · 2012: 34
- FWCI
- 11.76
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Proceedings of the National Academy of Sciences (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Funders
- National Institutes of Health (DK 31127)
- National Institute of Diabetes and Digestive and Kidney Diseases (R56DK031127, R37DK031127, DK 065064, R01DK031127, Z01DK031127, K01DK065064)
- Topics
- Health Sciences › Medicine › Hematology › Iron Metabolism and Disorders
- Health Sciences › Nursing › Nutrition and Dietetics › Trace Elements in Health
- Life Sciences › Agricultural and Biological Sciences › Plant Science › Plant Micronutrient Interactions and Effects
- Keywords
- ZIP14, SLC39A14, non-transferrin-bound iron, iron absorption, zinc transporters, ferrous iron, metallothionein, hepatocytes, hemochromatosis, transfusional iron overload, inflammation
- MeSH terms
- Animals, Biological Transport, Cell Membrane, Cells, Cultured, Humans, Iron, Metallothionein, RNA, Messenger, Tissue Distribution, Transferrin, Zinc, Hepatocytes, Cation Transport Proteins, RNA, Small Interfering, Mice
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