Intestine-specific deletion of metal transporter Zip14 (Slc39a14) causes brain manganese overload and locomotor defects of manganism

Abstract

Impaired manganese (Mn) homeostasis can result in excess Mn accumulation in specific brain regions and neuropathology. Maintaining Mn homeostasis and detoxification is dependent on effective Mn elimination. Specific metal transporters control Mn homeostasis. Human carriers of mutations in the metal transporter ZIP14 and whole body Zip14-knockout (WB-KO) mice display similar phenotypes, including spontaneous systemic and brain Mn overload and motor dysfunction. Initially, it was believed that Mn accumulation due to ZIP14 mutations was caused by impaired hepatobiliary Mn elimination. However, liver-specific Zip14-KO mice did not show systemic Mn accumulation or motor deficits. ZIP14 is highly expressed in the small intestine and is localized to the basolateral surface of enterocytes. Thus, we hypothesized that basolaterally localized ZIP14 in enterocytes provides another route for the elimination of Mn. Using wild-type and intestine-specific Zip14-KO (I-KO) mice, we have shown that ablation of intestinal Zip14 is sufficient to cause systemic and brain Mn accumulation. The lack of intestinal ZIP14-mediated Mn excretion was compensated for by the hepatobiliary system; however, it was not sufficient to maintain Mn homeostasis. When supplemented with extra dietary Mn, I-KO mice displayed some motor dysfunctions and brain Mn accumulation based on both MRI imaging and chemical analysis, thus demonstrating the importance of intestinal ZIP14 as a route of Mn excretion. A defect in intestinal Zip14 expresssion likely could contribute to the Parkinson-like Mn accumulation of manganism. NEW & NOTEWORTHY Mn-induced parkinsonism is recognized as rising in frequency because of both environmental factors and genetic vulnerability; yet currently, there is no cure. We provide evidence in an integrative animal model that basolaterally localized ZIP14 regulates Mn excretion and detoxification and that deletion of intestinal ZIP14 leads to systemic and brain Mn accumulation, providing robust evidence for the indispensable role of intestinal ZIP14 in Mn excretion.

The Functions of ZIP8, ZIP14, and ZnT10 in the Regulation of Systemic Manganese Homeostasis

“…To determine the physiological relevance of these findings, intestine-specific Zip14 knockout mice (Zip14-In-KO) were generated. In contrast to Zip14-L-KO mice that did not develop manganese overload in the body, Zip14-In-KO mice developed increased manganese in both the liver and brain under normal dietary conditions, verifying the importance of intestinal ZIP14 in maintaining systemic manganese homeostasis [66,67]. Based on the results from these most recent studies, we propose a new model for the function of ZIP14 in regulating systemic manganese homeostasis that includes the functions of intestinal ZIP14 to limit dietary manganese absorption and hepatic ZIP14 to clear manganese from the portal blood (Figure 2A,B).…”

Molecular Targets of Manganese-Induced Neurotoxicity: A Five-Year Update

“…It has been proposed that modulation of ZIP14 may be involved in prevention of Mn-induced neurotoxicity [ 34 ]. A study in intestine-specific ZIP14-KO demonstrated that intestinal ZIP14 deficiency is responsible for systemic and brain Mn accumulation upon overexposure and cannot be compensated by hepatobiliary metal excretion [ 35 ]. ZIP14 deficiency in ZIP14 knock-out (KO) mice resulted in reduced Mn excretion after subcutaneous Mn administration as well as increased cerebral Mn accumulation with subsequent motor dysfunction [ 34 ].…”

Restriction of Manganese Intake Prevents the Onset of Brain Manganese Overload in Zip14−/− Mice

“…In addition to the hepatobiliary excretion route, the intestinal absorption also plays important role in regulating the systemic manganese homeostasis [8,27]. Previous studies have demonstrated that, differently from Zip14-L-KO mice that did not develop systemic manganese overload, Zip14-In-KO mice had increased manganese in both the liver and brain under normal dietary conditions [15,16], suggesting that lack-of-ZIP14 increases intestinal manganese absorption [15]. Therefore, we next sought to determine whether limiting manganese intake can prevent the development of manganese overload in Zip14 −/− mice.…”

“…However, even with reduced manganese uptake into the liver, Zip14-L-KO mice had normal manganese levels in the blood and other body tissues, suggesting that hepatic ZIP14 is not the primary control for systemic manganese homeostasis at physiological conditions [13,15]. In contrast to Zip14-L-KO mice that did not develop manganese overload in the body, mice with intestinal specific Zip14 knockout (Zip14-In-KO) developed increased manganese in both the liver and brain under normal dietary conditions, highlighting the importance of intestinal ZIP14 in maintaining systemic manganese homeostasis [15,16]. Taken together, these previous studies have confirmed an indispensable role for ZIP14 in regulating manganese homeostasis, because lack of ZIP14 leads to increased manganese absorption through the intestine [15] and impaired manganese clearance through hepatobiliary excretion [10,[12][13][14].…”