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ResearchIn-Press PreviewEndocrinologyGenetics Open Access | 10.1172/JCI187044

Stimulated thyroid hormone synthesis machinery drives thyrocyte cell death independent of ER stress

Crystal Young,1 Xiaohan Zhang,1 Xiaofan Wang,1 Aaron P. Kellogg,1 Kevin Pena,1 August Z. Cumming,1 Xiao-Hui Liao,2 Dennis Larkin,1 Hao Zhang,1 Emma Mastroianni,1 Helmut Grasberger,2 Samuel Refetoff,3 and Peter Arvan1

1Division of Metabolism, Endocrinology & Diabetes, University of Michigan School of Medicine, Ann Arbor, United States of America

2Department of Medicine, Division of Gastroenterology, University of Michigan School of Medicine, Ann Arbor, United States of America

3Department of Medicine, The University of Chicago, Chicago, United States of America

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1Division of Metabolism, Endocrinology & Diabetes, University of Michigan School of Medicine, Ann Arbor, United States of America

2Department of Medicine, Division of Gastroenterology, University of Michigan School of Medicine, Ann Arbor, United States of America

3Department of Medicine, The University of Chicago, Chicago, United States of America

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1Division of Metabolism, Endocrinology & Diabetes, University of Michigan School of Medicine, Ann Arbor, United States of America

2Department of Medicine, Division of Gastroenterology, University of Michigan School of Medicine, Ann Arbor, United States of America

3Department of Medicine, The University of Chicago, Chicago, United States of America

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1Division of Metabolism, Endocrinology & Diabetes, University of Michigan School of Medicine, Ann Arbor, United States of America

2Department of Medicine, Division of Gastroenterology, University of Michigan School of Medicine, Ann Arbor, United States of America

3Department of Medicine, The University of Chicago, Chicago, United States of America

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1Division of Metabolism, Endocrinology & Diabetes, University of Michigan School of Medicine, Ann Arbor, United States of America

2Department of Medicine, Division of Gastroenterology, University of Michigan School of Medicine, Ann Arbor, United States of America

3Department of Medicine, The University of Chicago, Chicago, United States of America

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1Division of Metabolism, Endocrinology & Diabetes, University of Michigan School of Medicine, Ann Arbor, United States of America

2Department of Medicine, Division of Gastroenterology, University of Michigan School of Medicine, Ann Arbor, United States of America

3Department of Medicine, The University of Chicago, Chicago, United States of America

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1Division of Metabolism, Endocrinology & Diabetes, University of Michigan School of Medicine, Ann Arbor, United States of America

2Department of Medicine, Division of Gastroenterology, University of Michigan School of Medicine, Ann Arbor, United States of America

3Department of Medicine, The University of Chicago, Chicago, United States of America

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1Division of Metabolism, Endocrinology & Diabetes, University of Michigan School of Medicine, Ann Arbor, United States of America

2Department of Medicine, Division of Gastroenterology, University of Michigan School of Medicine, Ann Arbor, United States of America

3Department of Medicine, The University of Chicago, Chicago, United States of America

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1Division of Metabolism, Endocrinology & Diabetes, University of Michigan School of Medicine, Ann Arbor, United States of America

2Department of Medicine, Division of Gastroenterology, University of Michigan School of Medicine, Ann Arbor, United States of America

3Department of Medicine, The University of Chicago, Chicago, United States of America

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1Division of Metabolism, Endocrinology & Diabetes, University of Michigan School of Medicine, Ann Arbor, United States of America

2Department of Medicine, Division of Gastroenterology, University of Michigan School of Medicine, Ann Arbor, United States of America

3Department of Medicine, The University of Chicago, Chicago, United States of America

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1Division of Metabolism, Endocrinology & Diabetes, University of Michigan School of Medicine, Ann Arbor, United States of America

2Department of Medicine, Division of Gastroenterology, University of Michigan School of Medicine, Ann Arbor, United States of America

3Department of Medicine, The University of Chicago, Chicago, United States of America

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1Division of Metabolism, Endocrinology & Diabetes, University of Michigan School of Medicine, Ann Arbor, United States of America

2Department of Medicine, Division of Gastroenterology, University of Michigan School of Medicine, Ann Arbor, United States of America

3Department of Medicine, The University of Chicago, Chicago, United States of America

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1Division of Metabolism, Endocrinology & Diabetes, University of Michigan School of Medicine, Ann Arbor, United States of America

2Department of Medicine, Division of Gastroenterology, University of Michigan School of Medicine, Ann Arbor, United States of America

3Department of Medicine, The University of Chicago, Chicago, United States of America

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Published October 14, 2025 - More info

J Clin Invest. https://doi.org/10.1172/JCI187044.
Copyright © 2025, Young et al. This work is licensed under the Creative Commons Attribution 4.0 International License. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.
Published October 14, 2025 - Version history
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Abstract

It is now recognized that patients and animal models expressing genetically-encoded misfolded mutant thyroglobulin (TG, the protein precursor for thyroid hormone synthesis) exhibit dramatic swelling of the endoplasmic reticulum (ER) with ER stress and cell death in thyrocytes — seen both in homozygotes (with severe hypothyroidism) and heterozygotes (with subclinical hypothyroidism). The thyrocyte death phenotype is exacerbated upon thyroidal stimulation (by thyrotropin, TSH), as cell death is inhibited upon treatment with exogenous thyroxine. TSH stimulation might contribute to cytotoxicity by promoting ER stress, or by an independent mechanism. Here we’ve engineered knockout mice completely lacking Tg expression. Like other animals/patients with mutant TG, these animals rapidly develop severe goitrous hypothyroidism; however, thyroidal ER stress is exceedingly low — lower even than that seen in wildtype mice. Nevertheless, mice lacking TG exhibit abundant thyroid cell death, which depends upon renegade thyroidal iodination — it is completely suppressed in a genetic model lacking effective iodination, or in Tg-KO mice treated with propylthiouracil (iodination inhibitor), or iodide deficiency. Thyrocytes in culture are killed not in the presence of H2O2 alone, but rather upon peroxidase-mediated iodination, with cell death blocked by propylthiouracil. Thus, in the thyroid gland bearing Tg mutation(s), TSH-stimulated iodination activity triggers thyroid cell death.

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Version history
  • Version 1 (October 14, 2025): In-Press Preview
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