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

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

Research output: Contribution to journalArticle

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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.

Original languageEnglish (US)
Pages (from-to)16605-16615
Number of pages11
JournalJournal of Biological Chemistry
Volume292
Issue number40
DOIs
StatePublished - 2017

Fingerprint

Manganese
Hypothyroidism
Thyroxine
Thyroid Gland
Liver
Brain
Detoxification
Blood
Knockout Mice
Phenotype
Gene encoding
Toxicity
Hepatocytes

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Biology
  • Cell Biology

Cite this

Liu, C., Hutchens, S., Jursa, T., Shawlot, W., Polishchuk, E. V., Polishchuk, R. S., ... Mukhopadhyay, S. (2017). Hypothyroidism induced by loss of the manganese efflux transporter SLC30A10 may be explained by reduced thyroxine production. Journal of Biological Chemistry, 292(40), 16605-16615. https://doi.org/10.1074/jbc.M117.804989

Hypothyroidism induced by loss of the manganese efflux transporter SLC30A10 may be explained by reduced thyroxine production. / Liu, Chunyi; Hutchens, Steven; Jursa, Thomas; Shawlot, William; Polishchuk, Elena V.; Polishchuk, Roman S.; Dray, Beth K.; Gore, Andrea C.; Aschner, Michael; Smith, Donald R.; Mukhopadhyay, Somshuvra.

In: Journal of Biological Chemistry, Vol. 292, No. 40, 2017, p. 16605-16615.

Research output: Contribution to journalArticle

Liu, C, Hutchens, S, Jursa, T, Shawlot, W, Polishchuk, EV, Polishchuk, RS, Dray, BK, Gore, AC, Aschner, M, Smith, DR & Mukhopadhyay, S 2017, 'Hypothyroidism induced by loss of the manganese efflux transporter SLC30A10 may be explained by reduced thyroxine production', Journal of Biological Chemistry, vol. 292, no. 40, pp. 16605-16615. https://doi.org/10.1074/jbc.M117.804989
Liu, Chunyi ; Hutchens, Steven ; Jursa, Thomas ; Shawlot, William ; Polishchuk, Elena V. ; Polishchuk, Roman S. ; Dray, Beth K. ; Gore, Andrea C. ; Aschner, Michael ; Smith, Donald R. ; Mukhopadhyay, Somshuvra. / Hypothyroidism induced by loss of the manganese efflux transporter SLC30A10 may be explained by reduced thyroxine production. In: Journal of Biological Chemistry. 2017 ; Vol. 292, No. 40. pp. 16605-16615.
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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.",
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AU - Polishchuk, Elena V.

AU - Polishchuk, Roman S.

AU - Dray, Beth K.

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