Differential Effects of 3,5-Diiodo-L-Thyronine and 3,5,3’-Triiodo-L-Thyronine On Mitochondrial Respiratory Pathways in Liver from Hypothyroid Rats

Abstract

Background/Aims: Both 3,5-diiodo-L-thyronine (3,5-T2) and 3,5,3’-triiodo-L-tyronine (T3) affect energy metabolism having mitochondria as a major target. However, the underlying mechanisms are poorly understood. Here, using a model of chemically induced hypothyroidism in male Wistar rats, we investigated the effect of administration of either 3,5-T2 or T3 on liver oxidative capacity through their influence on mitochondrial processes including: proton-leak across the mitochondrial inner membrane; complex I-, complex II- and glycerol-3-phosphate-linked respiratory pathways; respiratory complex abundance and activities as well as individual complex aggregation into supercomplexes. Methods: Hypothyroidism was induced by propylthiouracil and iopanoic acid; 3,5-T2 and T3 were intraperitoneally administered at 25 and 15 µg/100 g BW for 1 week, respectively. Resulting alterations in mitochondrial function were studied by combining respirometry, Blue Native-PAGE followed by in-gel activity, and Western blot analyses. Results: Administration of 3,5-T2 and T3 to hypothyroid (hypo) rats enhanced mitochondrial respiration rate with only T3 effectively stimulating proton-leak (450% vs. Hypo). T3 significantly enhanced complex I (+145% vs. Hypo), complex II (+66% vs. Hypo), and glycerol-3 phosphate dehydrogenase (G3PDH)-linked oxygen consumptions (about 6- fold those obtained in Hypo), while 3,5-T2 administration selectively restored Euthyroid values of complex II- and increased G3PDH- linked respiratory pathways (+165% vs. Hypo). The mitochondrial abundance of all respiratory complexes and of G3PDH was increased by T3 administration whereas 3,5-T2 only increased complex V and G3PDH abundance. 3,5-T2 enhanced complex I and complex II in gel activities with less intensity than did T3, and T3 also enhanced the activity of all other respiratory complexes tested. In addition, only T3 enhanced individual respiratory component complex assembly into supercomplexes. Conclusions: The reported data highlight novel molecular mechanisms underlying the effect elicited by iodothyronine administration to hypothyroid rats on mitochondrial processes related to alteration in oxidative capacity in the liver. The differential effects elicited by the two iodothyronines indicate that 3,5-T2, by influencing the kinetic properties of specific mitochondrial respiratory pathways, would promote a rapid response of the organelle, while T3, by enhancing the abundance of respiratory chain component and favoring the organization of respiratory chain complex in supercomplexes, would induce a slower and prolonged response of the organelle.

<p>Comparison of osteogenic differentiation induced by <em>siNoggin</em> and <em>pBMP-2</em> delivered by lipopolysaccharide-amine nanopolymersomes and underlying molecular mechanisms</p>

“…In the BMP/Smad signaling pathway, BMPs bind to and activate receptors to phosphorylate Smad/1/5/9 proteins, which further drives osteogenic differentiation. In the GSK-3β/β-catenin signaling pathway, inhibition of GSK-3β activity is a key step that protects β-catenin from degradation and leads to its accumulation in cytoplasm, and then β-catenin translocates to the nucleus to drive osteogenic differentiation 33,34. GSK-3 is a widely expressed and highly conserved serine/threonine protein kinase.…”

3,5-T2—A Janus-Faced Thyroid Hormone Metabolite Exerts Both Canonical T3-Mimetic Endocrine and Intracrine Hepatic Action

“…Most of these studies were performed in severely hypothyroid, mostly rat models, and 3,5-T2 doses were administered acutely as well as chronically. Unfortunately, no information had been published on 3,5-T2 concentrations reached in the circulation or in those target tissues like liver, where beneficial effects such as antisteatotic activity and increased lipid metabolism were reported (15,17,28,89,90). The first evidence for rapid T3-independent effects of 3,5-T2 on mitochondrial activity and oxygen consumption was provided by Horst et al (16), who observed rapid stimulation of oxygen consumption in isolated perfused livers, removed from hypothyroid rats.…”

3,5‐diiodo‐L‐thyronine increases de novo lipogenesis in liver from hypothyroid rats by SREBP‐1 and ChREBP‐mediated transcriptional mechanisms

“…In the present study, we followed in Hypo rats the effect on DNL of T2 at a dose (15 μg/100 g BW for 1 week) that was already demonstrated to be metabolically effective . Notably, considering serum thyroid hormone levels (Table ), it can be inferred that the observed T2 effects on DNL may be ascribed to a direct action of the diiodothyronine rather than to an indirect one due to its conversion to T3.…”