The TRβ-selective agonist, GC-1, stimulates mitochondrial oxidative processes to a lesser extent than triiodothyronine

Abstract

Specific tissue responses to thyroid hormone are mediated by the hormone binding to two subtypes of nuclear receptors, TRa and TRb. We investigated the relationship between TRb activation and liver oxidative metabolism in hypothyroid rats treated with equimolar doses of triiodothyronine (T 3 ) and GC-1, a TRb agonist. T 3 treatment produces increases in O 2 consumption and H 2 O 2 production higher than those elicited by GC-1. The greater effects of T 3 on oxidative processes are linked to the higher hormonal stimulation of the content of respiratory chain components including autoxidizable electron carriers as demonstrated by the measurement of activities of respiratory complexes and H 2 O 2 generation in the presence of respiratory inhibitors. It is conceivable that these differential effects are dependent on the inability of GC-1 to stimulate TRa receptors that are likely involved in the expression of some components of the respiratory chain. The greater increases in reactive oxygen species production and susceptibility to oxidants exhibited by mitochondria from T 3 -treated rats are consistent with their higher lipid and protein oxidative damage and lower resistance to Ca 2C load. The T 3 and GC-1 effects on the expression levels of nuclear respiratory factor-1 and -2 and peroxisome proliferatoractivated receptor-g coactivator-1a suggest the involvement of respiratory factors in the agonist-linked changes in mitochondrial respiratory capacities and H 2 O 2 production.

Effect of thyroid state on enzymatic and non-enzymatic processes in H2O2 removal by liver mitochondria of male rats

“…However, it is not known whether conditions leading to increased cellular ROS production also involve changes in mitochondrial capacity to remove H2O2. Previously, we found that the capacity of non respiring mitochondria from rat liver is modified by thyroid state, being high in hyperthyroid and low in hypothyroid state (Venditti et al, 2010). This pattern is confirmed by present results, which also show that, in all thyroid states, H2O2 removal significantly increases in the presence of respiratory substrates, in particular pyruvate/malate, even though the highest and the lowest removal rates are yet found in hyperthyroid and in hypothyroid state, respectively.…”

“…Because GSH contributes to H2O2 mitochondrial metabolism as co-factor of both glutathione peroxidase and peroxiredoxins, we determined its mitochondrial content, which was found to be independent of thyroid state, confirming previous report (Venditti et al, 2010). Interestingly, decreases in GSH mitochondrial content were reported in hyperthyroidism induced by administering T3 to euthyroid rats (Chattopadhai et al, 2010;Venditti et al, 2006), even though we are not able to provide straightforward explanation for this.…”

Thyroid hormone status defines brown adipose tissue activity and browning of white adipose tissues in mice

“…Findings from different TR knockout mice (e.g. TRα, TRβ, TRα1+m) and the use of isoform-selective agonists indicate specific roles for TH-adrenergic interactions in BAT and white adipose tissue(WAT)45678910. Early studies in thyroidectomized and hypothyroid rats demonstrated the relevance of BAT specific type II iodothyronine deiodinase Dio2 as a local and systemic source of 3,3′,5-triiodothyronine (T 3 ) under cold exposure and for the first time provided evidence for T 3 in the enhancement of the thermogenic response to sympathetic stimulation1112.…”

Lipid peroxidation in kidney and testis tissues in experimental hypothyroidism: the role of zinc

“…It has been established in various studies that the changes in thyroid hormone metabolism affect oxidant and antioxidant systems in different ways. Venditti et al (6) reported that T 3 treatment increased oxygen consumption and H 2 O 2 production, while Cano-Europa and colleagues (7) found that hypothyroidism induced by methimazole or thyroidectomy caused cellular damage in rats and that this damage could not be corrected by antioxidant systems. However, it was also established in another study that the effect caused by propylthiouracil (PTU) administration on the oxidant and antioxidant systems changed in a time-dependent manner (8).…”