Abstract
The alveolar epithelia of the lungs require manganese (Mn) as an essential nutrient, but also provide an entry route for airborne Mn that can cause neurotoxicity. Transporters involved in Mn uptake by alveolar epithelial cells are unknown. Recently, two members of the Zrt- and Irt-like protein (ZIP) family of metal transporters, ZIP8 and ZIP14, have been identified as crucial Mn importers in vivo. ZIP8 is by far most abundantly expressed in the lungs, whereas ZIP14 expression in the lungs is low compared to other tissues. We hypothesized that Mn uptake by alveolar epithelial cells is primarily mediated by ZIP8. To test our hypothesis, we used A549 cells, a type II alveolar cell line. Mirroring the in vivo situation, A549 cells expressed higher levels of ZIP8 than cell models for the liver, intestines, and kidney. Quantification of ZIP8 and ZIP14 revealed a strong enrichment of ZIP8 over ZIP14 in A549 cells. Using siRNA technology, we identified ZIP8 and ZIP14 as the major transporters mediating Mn uptake by A549 cells. To our surprise, knockdown of either ZIP8 or ZIP14 impaired Mn accumulation to a similar extent, which we traced back to similar amounts of ZIP8 and ZIP14 at the plasma membrane. Our study highlights the importance of both ZIP8 and ZIP14 in Mn metabolism of alveolar epithelial cells.
Highlights
IntroductionManganese (Mn) is an essential nutrient required for the normal function of several physiologic processes including protein glycosylation, defense against oxidative stress, and gluconeogenesis [1,2]
Manganese (Mn) is an essential nutrient required for the normal function of several physiologic processes including protein glycosylation, defense against oxidative stress, and gluconeogenesis [1,2].Yet, excess Mn is neurotoxic, and elevated accumulation in the brain may result in manganism, an extrapyramidal disorder whose symptoms resemble those of Parkinson’s disease [3,4].Under normal conditions, oral exposure is the major source for Mn absorption [5]
As these cells may differ in their transporter expression, we first assessed whether A549 cells, a Type II alveolar cell line, provided a transporters employing the fusion-peptides used to generate the respective antibodies as quantitative markers (Figure S3)
Summary
Manganese (Mn) is an essential nutrient required for the normal function of several physiologic processes including protein glycosylation, defense against oxidative stress, and gluconeogenesis [1,2]. Oral exposure is the major source for Mn absorption [5]. Manganese entering the body via this route is tightly controlled by regulating intestinal Mn absorption and hepatobiliary Mn excretion [6,7,8,9]. Chronic Mn toxicity due to the gastrointestinal absorption in individuals with no genetic susceptibility is not a major public health concern [10]. Individuals exposed to high levels of airborne Mn, such as welders or miners that are exposed to
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