Hypothyroidism induced by loss of the manganese efflux transporter SLC30A10 may be explained by reduced thyroxine production

Steven Hutchens,Andrea C Gore,Elena V Polishchuk,Donald R Smith,Michael Aschner,Chunyi Liu,Somshuvra Mukhopadhyay,William Shawlot,Beth K Dray,Thomas Jursa,Roman S Polishchuk

doi:10.1074/jbc.m117.804989

Abstract

SLC30A10 and SLC39A14 are manganese efflux and influx transporters, respectively. Loss-of-function mutations in genes encoding either transporter induce hereditary manganese toxicity. Patients have elevated manganese in the blood and brain and develop neurotoxicity. Liver manganese is increased in patients lacking SLC30A10 but not SLC39A14. These organ-specific changes in manganese were recently recapitulated in knockout mice. Surprisingly, Slc30a10 knockouts also had elevated thyroid manganese and developed hypothyroidism. To determine the mechanisms of manganese-induced hypothyroidism and understand how SLC30A10 and SLC39A14 cooperatively mediate manganese detoxification, here we produced Slc39a14 single and Slc30a10/Slc39a14 double knockout mice and compared their phenotypes with that of Slc30a10 single knockouts. Compared with wild-type controls, Slc39a14 single and Slc30a10/Slc39a14 double knockouts had higher manganese levels in the blood and brain but not in the liver. In contrast, Slc30a10 single knockouts had elevated manganese levels in the liver as well as in the blood and brain. Furthermore, SLC30A10 and SLC39A14 localized to the canalicular and basolateral domains of polarized hepatic cells, respectively. Thus, transport activities of both SLC39A14 and SLC30A10 are required for hepatic manganese excretion. Compared with Slc30a10 single knockouts, Slc39a14 single and Slc30a10/Slc39a14 double knockouts had lower thyroid manganese levels and normal thyroid function. Moreover, intrathyroid thyroxine levels of Slc30a10 single knockouts were lower than those of controls. Thus, the hypothyroidism phenotype of Slc30a10 single knockouts is induced by elevated thyroid manganese, which blocks thyroxine production. These findings provide new insights into the mechanisms of manganese detoxification and manganese-induced thyroid dysfunction.

Highlights

SLC30A10 and SLC39A14 are manganese efflux and influx transporters, respectively
Our results show that SLC39A14 and Manganese levels are elevated in the blood and brain, but not liver, of Slc39a14 single and Slc30a10/Slc39a14 double knockouts
We demonstrated previously that manganese levels were elevated in the brain, pituitary, and thyroid of Slc30a10 single knockout mice [22]

Summary

Introduction

SLC30A10 and SLC39A14 are manganese efflux and influx transporters, respectively. Loss-of-function mutations in genes encoding either transporter induce hereditary manganese toxicity. Slc30a10 single knockouts had elevated manganese levels in the liver as well as in the blood and brain. The hypothyroidism phenotype of Slc30a10 single knockouts is induced by elevated thyroid manganese, which blocks thyroxine production. In 2012, homozygous loss of function mutations in SLC30A10 were reported to increase manganese levels in the blood, brain, and liver and induce neurotoxicity (18 –21). We recently reported that similar increases in blood, brain, and liver manganese occurred in Slc30a10 knockout mice [22]. In 2016, mutations in SLC39A14 ( called ZIP14) were reported to increase manganese levels in the blood and brain (but not in the liver; see below) and induce neurotoxicity in humans [25].

Methods

Results

Conclusion