SLC39A14 deficiency alters manganese homeostasis and excretion resulting in brain manganese accumulation and motor deficits in mice

Abstract

Solute carrier family 39, member 14 (SLC39A14) is a transmembrane transporter that can mediate the cellular uptake of zinc, iron, and manganese (Mn). Studies of knockout () mice have documented that SLC39A14 is required for systemic growth, hepatic zinc uptake during inflammation, and iron loading of the liver in iron overload. The normal physiological roles of SLC39A14, however, remain incompletely characterized. Here, we report that mice spontaneously display dramatic alterations in tissue Mn concentrations, suggesting that Mn is a main physiological substrate for SLC39A14. Specifically, mice have abnormally low Mn levels in the liver coupled with markedly elevated Mn concentrations in blood and most other organs, especially the brain and bone. Radiotracer studies using Mn reveal that mice have impaired Mn uptake by the liver and pancreas and reduced gastrointestinal Mn excretion. In the brain of mice, Mn accumulated in the pons and basal ganglia, including the globus pallidus, a region susceptible to Mn-related neurotoxicity. Brain Mn accumulation in mice was associated with locomotor impairments, as assessed by various behavioral tests. Although a low-Mn diet started at weaning was able to reverse brain Mn accumulation in mice, it did not correct their motor deficits. We conclude that SLC39A14 is essential for efficient Mn uptake by the liver and pancreas, and its deficiency results in impaired Mn excretion and accumulation of the metal in other tissues. The inability of Mn depletion to correct the motor deficits in mice suggests that the motor impairments represent lasting effects of early-life Mn exposure.

Impact of dietary manganese on experimental colitis in mice

“…In our Mn supplementation study, we fed mice with 300 ppm Mn and found a slight protective effect against DSS‐induced colitis. Previous mouse studies have shown that oral supplementation with Mn even at levels of ~2400 ppm does not cause toxicity . This finding suggests that Mn toxicity would be less of a concern in the design of dietary Mn supplementation for this IBD mouse model.…”

“…Previous mouse studies have shown that oral supplementation with Mn even at levels of ~2400 ppm does not cause toxicity. 51,52 This finding suggests that Mn toxicity would be less of a concern in the design of dietary Mn supplementation for this IBD mouse model. Future studies will be needed to determine the dietary Mn levels that would be most beneficial for human patient populations.…”

Movement Disorders in Treatable Inborn Errors of Metabolism

“…Even more recently, a syndrome of infantile‐ or childhood‐onset dystonia with hypermanganesemia (OMIM #617013) has been linked to biallelic mutations in yet another divalent cation transporter gene, SLC39A14 , responsible for manganese elimination . This disorder presents in infancy or early childhood with developmental delay, dystonia, and bulbar dysfunction .…”

Distributions of manganese in diverse human cancers provide insights into tumour radioresistance

“…We did so since there are important gene expression data on metal transporters that modulate influx and efflux of Mn from the gastrointestinal tract after dietary ingestion and its release into the bloodstream. 23,24 The amount of Mn available to a tumour, be it at primary or metastatic sites, will initially be determined by how much Mn passes through this gateway into the bloodstream. Laser ablation was carried out on a standard glass slide on which an unstained section of patient material, derived from a tissue microarray, had been cut at 5 mm thickness from a formalin-fixed paraffin-embedded (FFPE) block.…”

“…This dual system controls Mn levels in the blood via the influx and efflux metal transporters in the liver and bile duct epithelium: predominantly via SLC39A14 (Mn uptake by the liver) and SLC30A10 (Mn efflux via the bile duct epithelium). 23,24 If these transporters are altered by mutation, allelic variants, or regulatory elements, the level of Mn in the blood is changed. When this occurs, dietary Mn uptake by the liver is reduced, more Mn is directed into the blood, and higher than normal concentrations accumulate in organs such as the brain.…”