Endocrinol Metab.  2021 Oct;36(5):952-964. 10.3803/EnM.2021.1198.

Deiodinases and the Three Types of Thyroid Hormone Deiodination Reactions

• Sabatino L
• Vassalle C
• Del Seppia C
• Iervasi G

• KMID: 2521943
• DOI: http://doi.org/10.3803/EnM.2021.1198

Abstract

Thyroid hormone (TH) signaling is strictly regulated by iodothyronine deiodinase activity, which both preserves the circulating levels of the biologically active triiodothyronine (T3) and regulates TH homeostasis at the local level, in a cell- and time-dependent manner. Three deiodinases have been identified—namely iodothyronine deiodinase 1 (DIO1), DIO2, and DIO3—that differ in their catalytic properties and tissue distribution. The deiodinases represent a dynamic system that changes in the different stages of life according to their functions and roles in various cell types and tissues. Deiodinase activity at the tissue level permits cell-targeted fine regulation of TH homeostasis, mediating the activation (DIO1 and DIO2) and inactivation (DIO3) of THs. Deiodinase homeostasis is the driving force that leads T3-target cells towards customized TH signaling, which takes into account both the hormonal circulating levels and the tissue-specific response. This review analyzes the complex role of deiodinases in physiological and pathological contexts, exploring new challenges and opportunities deriving from a deeper knowledge of the dynamics underlying their roles and functions.

Keyword

Deiodinases; Euthyroid sick syndromes; Hypoxia; Polymorphisms; Oxidative stress

Figure

• 

  Fig. 1 Schematic representation of the cellular location of deiodinases and genomic/non-genomic actions of thyroid hormones on cardiomyocytes. The three enzymes have different subcellular locations: iodothyronine deiodinase 1 (DIO1) and DIO3 are at the plasma membrane, whereas DIO2 is found at the endoplasmic reticulum membrane, which makes the enzyme very proximal to the nucleus. Genomic effects: thyroid receptors (TRs) mediate the direct effects of triiodothyronine (T3) and interactions with thyroid-responsive element (TRE) sequences on gene promoters. The main genomic effects on cardiac contractility occur by regulation of myosin heavy chains (MHC) α and β and through positive regulation by sarco/endoplasmic reticulum Ca2+ adenosine triphosphatase-2a (SERCA2a) and downregulation by phospholamban (PLB). Non-genomic effects include the activation of sodium, potassium, and calcium membrane channels, stimulation of mitochondriogenesis and augmentation of cellular oxidative capacity, and interactions with various signaling pathways such as mitogen-activated protein kinase (MAPK) superfamily, including extracellular signal-regulated kinases (ERK) 1/2 and p38 MAPK, the upstream protein kinase C (PKC), as well as phosphoinositide 3-kinases (PI3K) and Akt. T4, thyroxine; OxS, oxidative stress.

• 

  Fig. 2 Schematic representation of main events associated with iodothyronine deiodinase 3 (DIO3) activation and thyroid hormone dysfunction in cardiac remodeling after myocardial infarction (MI). Hypoxia induces DIO3 through hypoxia-inducible factor 1 (HIF-1) regulation and DIO3, in turn, promotes the low triiodothyronine (LT3) state in the heart. A set of upregulated miRNAs originating from the delta-like homolog 1-DIO3 (Dlk1)-Dio3 region is closely associated with MI progression. This miRNA signature, in turn, is associated with significant induction of DIO3 expression in the left ventricle of MI rats. Furthermore, the reduction of cardiac triiodothyronine (T3) induces miR-214, which exerts inhibitory effects on DIO3 expression in an attempt to restore T3 levels, thus having a protective function on infarcted myocardium. MHC, myosin heavy chain; SERCA, sarco/endoplasmic reticulum Ca2+ adenosine triphosphatase; PLB, phospholamban; MAPK, mitogen-activated protein kinase; OxS, oxidative stress.

• 

  Fig. 3 Schematic representation of the main events involving iodothyronine deiodinase 2 (DIO2) in the brain and discussed in the text: (1) DIO2 mRNA expression is induced in the parietal cortex after a hypotensive mechanical maneuver (double mandibular extension); (2) Triiodothyronine (T3) produced in the glial cells by DIO2 exerts paracrine-mediated signaling on the neurons; (3) The DIO2 Thr92Ala polymorphism is associated with impaired cognition and hypertension. T4, thyroxine.

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