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 September 17, 2019
Citation Information: J Clin Invest. 2019;129(12):5442-5461. https://doi.org/10.1172/JCI129710.
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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 5

Slc30a10 is essential for systemic and hepatobiliary Mn excretion.

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Slc30a10 is essential for systemic and hepatobiliary Mn excretion. Eight...
Eight-week-old Slc30a10+/+ and Slc30a10KO/KO mice were characterized for (A and B) fecal (A) and urinary (B) 54Mn levels after retro-orbital 54Mn injection and overnight housing in metabolic cages (data are presented as a percentage of total 54Mn); (C and D) biliary Mn levels normalized to liver weight (C) and Mn content (D) (in D, biliary Mn levels from WT mice on a control or high-Mn diet are included for reference); and (E) biliary copper levels. (F–H) Mice underwent bile duct ligation, gallbladder cannulation, 54Mn/fluorescein injection into the portal vein, and bile collection for 2 hours. (F) Blood and liver 54Mn levels. (G and H) Bile volume (G) and biliary 54Mn levels (H) versus time for female (left) and male (right) mice. Each data point represents the mean ± SEM. Values shown in G and H indicate the average slope of the line ± SEM for each group followed by a P value for comparison of line slopes by linear regression. In A–F, data are presented as individual values and represent the mean ± SEM. Outliers (not shown) were identified by ROUT. Two-tailed P values were calculated by unpaired t test. No outliers were identified in A–C, E, or F. Removal of the outlier in D did not alter the identification of comparisons with a P value below 0.05. For all panels, n = 5 replicates/group, except for females on a high-Mn diet (n = 4). *P < 0.05, **P < 0.01, ***P < 0.001, and ****P < 0.0001.