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

Abstract

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 <i>SLC39A14</i> gene have been linked to manganese (Mn) accumulation in the brain and childhood-onset parkinsonism dystonia. It has therefore been suggested that <i>SLC39A14</i> 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 <i>Slc39a14</i>-knockout (<i>Slc39a14</i>^<i>-/-</i> ) mice and hepatocyte-specific <i>Slc39a14</i>-knockout (<i>Slc39a14</i>^<i>fl/fl</i><i>;Alb-Cre</i>^<i>+</i> ) mice. <i>Slc39a14</i>^<i>-/-</i> 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, <i>Slc39a14</i>^<i>fl/fl</i><i>;Alb-Cre</i>^<i>+</i> mice do not accumulate Mn in the brain or other extrahepatic tissues and do not develop motor deficits, indicating that the loss of <i>Slc39a14</i> expression selectively in hepatocytes is not sufficient to cause Mn accumulation. Interestingly, <i>Slc39a14</i>^<i>fl/fl</i><i>;Alb-Cre</i>^<i>+</i> 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 <i>Slc39a14</i>^<i>-/-</i> mice develop brain Mn accumulation and motor deficits that cannot be explained by a loss of <i>Slc39a14</i> expression in hepatocytes. These findings provide insight into the physiological role that SLC39A14 has in maintaining Mn homeostasis. Our tissue-specific <i>Slc39a14</i>-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.