Manganese transporter Slc39a14 deficiency revealed its key role in maintaining manganese homeostasis in mice

Yongjuan Xin,Ruochen Zhang,Hao Wang,Yang Li,Yuming Xu,Hong Gao,Shintaro Hojyo,Jianyao Wang,Yuzhen Qiang,Yingying Yu,Haiyang Luo,Mustapha Umar Imam,Junxia Min,Fudi Wang,Jia Wang,Toshiyuki Fukada,Changhe Shi,Huizhen Zhang

doi:10.1038/celldisc.2017.25

Yongjuan Xin, Ruochen Zhang + Show 16 more

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https://doi.org/10.1038/celldisc.2017.25

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SLC39A14 (also known as ZIP14), a member of the SLC39A transmembrane metal transporter family, has been reported to mediate the cellular uptake of iron and zinc. Recently, however, mutations in the SLC39A14 gene have been linked to manganese (Mn) accumulation in the brain and childhood-onset parkinsonism dystonia. It has therefore been suggested that SLC39A14 deficiency impairs hepatic Mn uptake and biliary excretion, resulting in the accumulation of Mn in the circulation and brain. To test this hypothesis, we generated and characterized global Slc39a14-knockout (Slc39a14−/−) mice and hepatocyte-specific Slc39a14-knockout (Slc39a14fl/fl;Alb-Cre+) mice. Slc39a14−/− mice develop markedly increased Mn concentrations in the brain and several extrahepatic tissues, as well as motor deficits that can be rescued by treatment with the metal chelator Na2CaEDTA. In contrast, Slc39a14fl/fl;Alb-Cre+ mice do not accumulate Mn in the brain or other extrahepatic tissues and do not develop motor deficits, indicating that the loss of Slc39a14 expression selectively in hepatocytes is not sufficient to cause Mn accumulation. Interestingly, Slc39a14fl/fl;Alb-Cre+ mice fed a high Mn diet have increased Mn levels in the serum, brain and pancreas, but not in the liver. Taken together, our results indicate that Slc39a14−/− mice develop brain Mn accumulation and motor deficits that cannot be explained by a loss of Slc39a14 expression in hepatocytes. These findings provide insight into the physiological role that SLC39A14 has in maintaining Mn homeostasis. Our tissue-specific Slc39a14-knockout mouse model can serve as a valuable tool for further dissecting the organ-specific role of SLC39A14 in regulating the body’s susceptibility to Mn toxicity.

Highlights

In the body, metal homeostasis is a complex process involving multiple transporters that are tightly regulated by the levels of their substrates and/or other environmental conditions
The Slc39a14−/− mice developed motor deficits beginning at 16 weeks of age, with significant differences in duration of running time (Figure 1h), average running speed (Figure 1i), time of right forelimb (RF) stand (Figure 1j), right forelimb (RF) and left hindlimb (LH) swing speed (Figure 1k and l) compared with wild-type littermates
We characterized the role of the metal ion transporter Slc39a14 in systemic Mn metabolism using both global Slc39a14-knockout and hepatocytespecific Slc39a14-knockout mice

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Introduction

Metal homeostasis is a complex process involving multiple transporters that are tightly regulated by the levels of their substrates and/or other environmental conditions. Mutations in the hepatic metal ion transporter SLC39A8 have been linked to low blood Mn levels as well as several other human phenotypic traits. Lin et al showed that both Slc39a8-knockout mice and mice in which Slc39a8 expression is deleted in the liver develop significantly decreased tissue Mn levels [13]. Mn concentration is tightly regulated by the coordinated absorption and excretion of Mn [5]. Mn is excreted primarily via biliary and pancreatic secretion into the caudal sections of the gastrointestinal tract [25, 26], which help regulate the body’s Mn levels by adjusting the rate of elimination [27]

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