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The discovery of a novel protein in regulating manganese metabolism

 Ningning Zhao, University of Arizona, USA

 Manganese is essential for life. Tight homeostatic regulation is required to prevent manganese deficiency and avoid manganese overload. ZIP14 is a newly identified manganese importer. It is abundantly expressed in the liver and small intestine, the two major organs involved in the control of manganese metabolism. Patients with loss-of-function mutations in ZIP14 developed severe childhood-onset neurological disorder due to manganese hyper-accumulation in the brain; similarly, mice with whole-body Zip14 knockout displayed manganese loading in the blood and brain, indicating an indispensable role for ZIP14 in maintaining systemic Mn homeostasis. Through the deletion of ZIP14 in enterocytes, we have identified ZIP14 as the major transporter mediating basolateral manganese uptake. Lack of ZIP14 severely impaired basolateral-to-apical manganese transport, but strongly enhanced manganese transport in the apical-to-basolateral direction. Mechanistic studies demonstrated that ZIP14 limits manganese absorption via direct reuptake of freshly absorbed manganese. we propose a novel model for the control of systemic manganese homeostasis by ZIP14 that takes into account both manganese absorption by enterocytes and manganese clearance from the portal blood by hepatocytes.