Control of systemic manganese homeostasis by metal transporter ZIP14

Abstract

The trace element manganese is an essential nutrient. The homeostatic control of manganese within the body is critical for normal health. Two organs in the body—the liver and intestine—play important roles in this control. ZIP14 is a newly identified manganese importer. It is highly expressed in the liver and small intestine. Patients with ZIP14 mutations developed early-onset neurological disorder due to manganese overload in the brain; likewise, mice with whole-body Zip14 knockout displayed manganese accumulation in the blood and brain, indicating that ZIP14 possesses an indispensable role in maintaining systemic manganese homeostasis. However, the precise mechanism underlying manganese overload caused by ZIP14 deficiency remains unclear. We generated tissue-specific Zip14 knockout mice to examine the functions of ZIP14 in the liver and intestine. Our results demonstrated that liver specific Zip14 knockout mice did not develop systemic manganese overload. However, intestine-specific inactivation of Zip14 increased body manganese loading, suggesting that intestinal ZIP14 plays an important role in controlling the whole body manganese homeostasis. Our results provide novel insight into the disease mechanism underlying manganese hyperaccumulation associated with the lack of ZIP14.