Table 1.

Main selenoproteins associated with thyroid hormones functions, antioxidant defense, cellular distribution, and associated pathologies in case of Se deficiency.

Selenoproteins Relevant to Thyroid Health		Cellular Distribution Within Thyroid	Functions Under Optimal Conditions	Thyroid and Other Pathologies Associated with the Respective Selenoprotein Deficiency/Abnormality
Iodothyronine deiodinase (DIO)	DIO1	Plasma membrane	Converts inactive thyroxine (T4) to the biologically active triiodothyronine (T3) thyroid form, and control circulating T3 levels	DIO1 knockout mice had normal growth, development, and fertility, however they exhibited aberrant circulating TH and excretory iodothyronines [53,58]. Se deficiency in chickens inhibited the levels of DIO1, DIO2 and DIO3, which indirectly suppressed the conversion of T4 to T3 [59].
	DIO2	ER membrane	Intracellular conversion of T4 to T3 in thyrocytes, contributing to the major source of T3 in circulation in euthyroidism	DIO2 knockout mice exhibited impaired thermogenesis, brain function, transient growth retardation, in addition to aberrant circulating TH [53,60].
	DIO3	Plasma membrane	Inactivates thyroid hormones from T4 to reverse T3 (rT3), and T3 to T2	Fetal DIO3 knockout in mice is significant among all DIOs. It was characterised by reduced viability, growth retardation, impaired fertility, and hypothyroid symptoms, along with reduced T3 and increased T4 levels in the circulation [53]
Glutathione peroxidase (GPX)	GPX1	Cytosol	Protection against oxidative stress through reduction of H2O2 and lipid hydroperoxides	Reduced Se-dependent GPX activity, leading to diffusion of H2O2 into the thyroid parenchyma, followed by local inflammation and ultimately its destruction [61,62]
	GPX2	Not expressed in thyroid	Expression is specific to epithelial cells including colonic crypts and that in gastrointestinal tract and lungs, which offers protection against ingested lipid hydroperoxides [63]	N/A to thyroid health. However, GPX2 was suggested to be the most important Se-dependent antioxidant in colon and early defense against colon cancer [63]. Although no negative impacts of Se deficiency have been illustrated in humans, GPX2 knockout mice when deprived in Se showed enhanced ileocolitis (inflammation) in the intestinal mucosa than that of Se sufficiency [64].
	GPX3	Thyroid colloid (apical side of thyrocyte membrane)	Antioxidant in extracellular fluid; thyroid protection from excessive H2O2 in thyrocytes and follicular lumen, which is not used by thyroid peroxidase (TPO) for the iodination of thyroglobulin during the process of thyroid hormone synthesis	Se deficiencies reduced Se-dependent GPX activity, leading to diffusion of H2O2 into the thyroid parenchyma, followed by local inflammation and ultimately its destruction [61,62] In a Taiwanese population, SNPs in GPX3 were significantly associated with the risk of differentiated thyroid cancer [65]
	GPX4	Mitochondria	Reduction of phospholipid hydroperoxides in mitochondria, offering protection of mitochondrial membrane in thyrocytes against peroxidation [61,66] Modulate apoptosis	Limited information on the effects of GPX abnormalities on thyroid function. In Se-deficient mice, GPX4 activity was not significantly reduced when compared to that of GPX1 that had a 50% reduction [67]. Interestingly, embryonic mice with a full GPX4-gene deletion was fatal [68].
Thioredoxin reductase (TXNRD)	TXNRD1	Cytosol	Antioxidant by catalysing NADPH-dependent reduction of thioredoxin, regulating the intracellular redox environment	Limited data on the biological effects of TXNRD abnormalities on thyroid function. However, Se deficiency in mice caused a 4.5% and 11% reduction in TXNRD activity in liver and kidney respectively, while TXNRD level was unchanged [69]. It was postulated that the lack of Sec interferes with the biosynthesis of TXNRD and incorporation into the polypeptide chain at termination, which ultimately produces a non-functional protein [70].
	TXNRD2	Mitochondria	Regulate cell proliferation