Substrate for Thyroid Hormone Synthesis: Biochemistry, Evolution, and Physiology

The use of iodotyrosines to control development and other biological processes predates the evolution of the thyroid gland. Endogenous thyroid hormone synthesis evolved with the ability to enzymatically iodinate protein secreted and directed for gastrointestinal proteolysis-and evolved further to specialize for iodination of protein entrapped extracellularly within closed follicles. The evolutionary appearance of the vertebrate thyroid gland with its follicular architecture correlates closely with the first appearance of thyroglobulin, which acts as the primary protein scaffold for thyroid hormone synthesis. Thyrocytes synthesize thyroglobulin in vast quantity, iodinating both hormonogenic and non-hormonogenic tyrosines on the protein in the follicular lumen, where it serves as the body's supply of stored iodide (mono- and di-iodotyrosine) as well as thyroid hormone (primarily T₄, thyroxine). Endocytic ingestion of follicular thyroglobulin for delivery to lysosomes proteolytically liberates these residues for T₄ release to the bloodstream as well as intrathyroidal iodide recycling. Humans bearing mutations impairing any steps leading to thyroglobulin iodination present with congenital hypothyroidism; nevertheless, untreated goitrous patients bearing bi-allelic mutation in thyroglobulin can still make thyroid hormone. Even as thyrocytes in such patients grow to form a goiter, many thyrocytes die in the setting of persistent thyroidal endoplasmic reticulum (ER) stress. Recently, mice with genetic deletion of thyroglobulin have been found to also exhibit net goiter growth but also substantial thyroid cell death despite the complete absence of thyroidal ER stress. These findings suggest the possibility of a surprising back-up mechanism in both patients and mouse models bearing bi-allelic thyroglobulin mutation, that can link the iodination machinery for thyroid hormone synthesis to thyroid cell death.