Manganese transporter Slc30a10 controls physiological manganese excretion and toxicity
Courtney J. Mercadante, … , Deepa B. Rao, Thomas B. Bartnikas
Courtney J. Mercadante, … , Deepa B. Rao, Thomas B. Bartnikas
Published December 2, 2019; First published September 17, 2019
Citation Information: J Clin Invest. 2019;129(12):5442-5461. https://doi.org/10.1172/JCI129710.
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Categories: Research Article Genetics Metabolism

Manganese transporter Slc30a10 controls physiological manganese excretion and toxicity

Abstract

Manganese (Mn), an essential metal and nutrient, is toxic in excess. Toxicity classically results from inhalational exposures in individuals who work in industrial settings. The first known disease of inherited Mn excess, identified in 2012, is caused by mutations in the metal exporter SLC30A10 and is characterized by Mn excess, dystonia, cirrhosis, and polycythemia. To investigate the role of SLC30A10 in Mn homeostasis, we first generated whole-body Slc30a10–deficient mice, which developed severe Mn excess and impaired systemic and biliary Mn excretion. Slc30a10 localized to canalicular membranes of hepatocytes, but mice with liver Slc30a10 deficiency developed minimal Mn excess despite impaired biliary Mn excretion. Slc30a10 also localized to the apical membrane of enterocytes, but mice with Slc30a10 deficiency in small intestines developed minimal Mn excess despite impaired Mn export into the lumen of the small intestines. Finally, mice with Slc30a10 deficiency in liver and small intestines developed Mn excess that was less severe than that observed in mice with whole-body Slc30a10 deficiency, suggesting that additional sites of Slc30a10 expression contribute to Mn homeostasis. Overall, these results indicated that Slc30a10 is essential for Mn excretion by hepatocytes and enterocytes and could be an effective target for pharmacological intervention to treat Mn toxicity.

Authors

Courtney J. Mercadante, Milankumar Prajapati, Heather L. Conboy, Miriam E. Dash, Carolina Herrera, Michael A. Pettiglio, Layra Cintron-Rivera, Madeleine A. Salesky, Deepa B. Rao, Thomas B. Bartnikas

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Figure 2

Slc30a10-deficient mice have increased RBC parameters and mild thyroid pathology.

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Slc30a10-deficient mice have increased RBC parameters and mild thyroid p...
Eight-week-old Slc30a10+/+, Slc30a10+/KO, and Slc30a10KO/KO mice were characterized for (A) blood Mn levels; (B) RBC counts; (C) hemoglobin levels; (D) hematocrit levels; (E) mean corpuscular volumes; (F) red cell distribution widths; and (G) thyroxine (T4) levels. For A–G, P values were calculated by 1-way ANOVA with Tukey’s multiple comparisons test. No outliers were identified by ROUT. Data are presented as individual values and represent the mean ± SEM. n = 5–9 replicates/group, except for female Slc30a10+/KO mice (n = 3–4). *P < 0.05, **P < 0.01, ***P < 0.001, and ****P < 0.0001. (H) Thyroid follicle area. Each vertical group represents 1 mouse, with each point representing 1 follicle (n = 21–96 follicles/mouse). The mean ± SEM for each mouse is shown with white bars and lines. The numbers above the groups represent the mean ± SEM for each sex and genotype. Two-tailed P values were calculated by nested t test. (I) H&E-stained images of thyroid. Original magnification, ×40; scale bars: 25 μm.