Abstract
As an essential nutrient, manganese is required for the regulation of numerous cellular processes, including cell growth, neuronal health, immune cell function, and antioxidant defense. However, excess manganese in the body is toxic and produces symptoms of neurological and behavioral defects, clinically known as manganism. Therefore, manganese balance needs to be tightly controlled. In the past eight years, mutations of genes encoding metal transporters ZIP8 (SLC39A8), ZIP14 (SLC39A14), and ZnT10 (SLC30A10) have been identified to cause dysregulated manganese homeostasis in humans, highlighting the critical roles of these genes in manganese metabolism. This review focuses on the most recent advances in the understanding of physiological functions of these three identified manganese transporters and summarizes the molecular mechanisms underlying how the loss of functions in these genes leads to impaired manganese homeostasis and human diseases.
Highlights
Manganese is an abundant element in the Earth’s crust and is naturally found in a variety of minerals [1]
ZIP14-deficient zebrafish hyper-accumulated manganese in the brain, but not in the liver, and presented with reduced locomotor activities [32]; whole-body Zip14 knockout mice (Zip14−/−) had markedly increased manganese levels in the blood and brain [62,63,64,65], resulting in impaired locomotor behavior, but had decreased liver manganese [62,64,65]. These results clearly demonstrate an indispensable role for ZIP14 in controlling systemic manganese homeostasis and suggest a model where lack of ZIP14 impairs manganese delivery to the liver and subsequent clearance through biliary excretion, which in turn lead to manganese accumulation in the blood and extrahepatic tissues, including the brain [32,62,63,65]
Hepatocyte-specific Zip14 knockout mice (Zip14-L-KO) had significantly decreased manganese in the liver, confirming the essential function for ZIP14 to import manganese to hepatocytes; even with reduced manganese uptake into the liver, Zip14-L-KO mice had normal manganese levels in the blood and other tissues [63,66]. These results indicate that hepatic ZIP14 is required for manganese delivery to the liver, the impaired hepatobiliary manganese excretion alone does not induce manganese hyper-accumulation in individuals lacking functional ZIP14, and suggest that ZIP14 in non-hepatic tissues acts as the primary control for systemic manganese homeostasis during normal physiological situations [63,66]
Summary
Manganese is an abundant element in the Earth’s crust and is naturally found in a variety of minerals [1]. Manganese is required for the function of numerous enzymes, including arginase, glycosyltransferases, manganese superoxide dismutase (MnSOD), phosphoenolpyruvate carboxykinase, prolidase, and pyruvate carboxylase [7,8,9,10]. Through these enzymes, manganese plays an important role in human health. Within the past eight years, mutations of genes encoding metal transporters ZIP8 (SLC39A8), ZIP14 (SLC39A14), and ZnT10 (SLC30A10) have been reported to cause dysregulated manganese homeostasis [18,30,31,32,33], demonstrating that the primary physiological function of these metal transporters is to regulate body manganese metabolism. We focus on the latest advances in the understanding of the physiological functions of these three manganese transporters and discuss the molecular mechanisms underlying dysregulated systemic manganese homeostasis caused by the deficiency of these genes
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