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 8

Hepatic Slc30a10 is essential for hepatobiliary Mn excretion.

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Hepatic Slc30a10 is essential for hepatobiliary Mn excretion. Four-month...
Four-month-old Slc30a10lox/lox and Slc30a10lox/lox Alb mice were analyzed for fecal (A), urinary (B), and liver and bile (C) 54Mn levels after 54Mn injection, overnight housing in metabolic cages, gallbladder cannulation, and 1-hour bile collection. Levels are expressed as a percentage of total 54Mn levels. (D) Total biliary Mn and copper levels, normalized to liver mass. (E and F) Another set of female (left) and male (right) mice underwent bile duct ligation, gallbladder cannulation, 54Mn/fluorescein injection via the portal vein, and 1-hour bile collection. (E) Biliary volumes. (F) Bile 54Mn levels. In A–D, data are presented as individual values and represent the mean ± SEM. Outliers (data not shown) were identified by ROUT. Two-tailed P values were calculated by unpaired t test. No outliers were detected in A–D. In E, each data point represent the mean ± SEM. Values shown in F indicate the average slope of the line ± SEM for each group followed by a P value for comparison of the line slopes by linear regression. For all panels, n = 4–7 replicates/group. *P < 0.05, **P < 0.01, and ***P < 0.001.