Recent progress toward understanding the role of ZIP14 in regulating systemic manganese homeostasis

Abstract

ZIP14 is a metal transporter essential for the regulation of body manganese homeostasis. The physiological functions of ZIP14 have been uncovered mainly through two lines of in vivo studies that examined the phenotypes of ZIP14 loss, including studies of humans with ZIP14 mutations and animals with ZIP14 deficiency. This mini review aims at presenting an updated view of the important advances made towards understanding the genetic and pathological mechanisms of brain manganese overload caused by ZIP14 deficiency.

Keywords: Manganese; Nutrition; SLC39A14; ZIP14.

Fig. 1

(A) Alphafold 3-dimensional representation of human ZIP14 membrane topology. (B) Two-dimensional representation of the Alphafold-predicted human ZIP14 protein. This model includes known ZIP14 mutations from patients with ZIP14 dysfunction and hypermanganesemia. The location of each mutation is represented, and each mutation is shown relative to transmembrane domains, N-linked glycosylation sites, and other relevant motifs. ZIP14 mutations were reported in the following sources: F98V, E105 * , S160Cfs* 5, G383R, N469K ; S104I ; R128W ; H251Pfs* 26 ; P379L ; N102D, L59Q, R108W, R128W, A432P, Y438C, Q61 * ; Q123 * , G171E . Among these mutations, F98V and G383R have been shown to reduce manganese transport activity by 80% compared to the wild-type ZIP14 .

Fig. 2

The intestine and liver are two main organs that control body manganese (Mn) metabolism. Dietary Mn travels through the intestine and is absorbed across the intestinal epithelium, collected by nearby capillaries, then delivered into the liver through the portal vein (PV). Nutrients in venous blood (blue dashed lines) are transported from the liver to the heart via the hepatic vein (HV). Blood and nutrients are returned to the liver, intestines, and other organs through arterial circulation (red dashed lines). In the liver, Mn is transported into the hepatocytes, exported into the bile, then returned to the small intestine (green dashed line). Mn and other nutrients in the intestine can be reabsorbed into blood or excreted in feces.

Fig. 3

ZIP14’s function in the liver. Liver ZIP14 localizes to the basolateral membrane (BL) of hepatocytes and its role is to import Mn into the hepatocytes from the blood. From the apical side (AP) of hepatocytes, Mn is transported into the bile by ZnT10 , , and then can be either reclaimed into hepatocytes by ZIP8 or delivered to the intestine through biliary secretion. The functions of ZIP8 and ZnT10 in manganese metabolism have been discussed in recent reviews , . An early model focused on ZIP14’s function in the liver to explain the development of brain Mn overload caused by ZIP14 loss: in individuals without functional ZIP14, Mn cannot be transported into hepatocytes, causing inefficient Mn excretion through the hepatobiliary route, and resulting in increased Mn in the blood and brain.

Fig. 4

ZIP14’s function in the intestine. A) Intestinal ZIP14 localizes to the basolateral membrane of enterocytes. Intestinal ZIP14 mediates the reuptake of freshly absorbed Mn from the blood to limit Mn absorption. Mn removed from the blood can enter the intestinal lumen to be reabsorbed or excreted. When the function of intestinal ZIP14 is blocked, the intestine lacks the regulatory mechanism to mediate the reuptake of absorbed Mn. The result is increased Mn concentrations in the blood and other body organs including the brain. This is the primary control of Mn homeostasis by ZIP14. B) When the function of hepatic ZIP14 is lacking, Mn cannot be transported into hepatocytes, causing inefficient Mn excretion through the hepatobiliary route, and resulting in increased Mn in the blood and other body organs only under high dietary intake conditions, but not under normal conditions. When Mn circulating through the blood is returned to the intestinal blood vessels (red dashed arrow), it can be efficiently cleared by intestinal ZIP14 under normal Mn intake conditions, but not under high Mn intake conditions, indicating that the primary Mn homeostatic control by intestinal ZIP14 can effectively balance body Mn without hepatic ZIP14 under normal conditions. Hepatic ZIP14 serves as the secondary control of Mn homeostasis by ZIP14.

Fig. 5

The mechanism underlying the systemic Mn overload caused by loss of ZIP14. When the functions of both intestinal ZIP14 and hepatic ZIP14 are blocked, such as conditions seen in patients with ZIP14 mutations, or in animals with whole-body Zip14 knockout, the body loses both primary and secondary controls of Mn homeostasis that need ZIP14. Mn concentrations will increase in the blood and other body organs including the brain. The liver Mn will decrease in this situation.