Effects of the thyroid hormone derivatives 3-iodothyronamine and thyronamine on rat liver oxidative capacity

Dipartimento delle Scienze Biologiche, Sezione di Fisiologia, Università di Napoli, I-80134 Napoli, Italy.
Molecular and Cellular Endocrinology (Impact Factor: 4.41). 06/2011; 341(1-2):55-62. DOI: 10.1016/j.mce.2011.05.013
Source: PubMed


Thyronamines T(0)AM and T(1)AM are naturally occurring decarboxylated thyroid hormone derivatives. Their in vivo administration induces effects opposite to those induced by thyroid hormone, including lowering of body temperature. Since the mitochondrial energy-transduction apparatus is known to be a potential target of thyroid hormone and its derivatives, we investigated the in vitro effects of T(0)AM and T(1)AM on the rates of O(2) consumption and H(2)O(2) release by rat liver mitochondria. Hypothyroid animals were used because of the low levels of endogenous thyronamines. We found that both compounds are able to reduce mitochondrial O(2) consumption and increase H(2)O(2) release. The observed changes could be explained by a partial block, operated by thyronamines, at a site located near the site of action of antimycin A. This hypothesis was confirmed by the observation that thyronamines reduced the activity of Complex III where the site of antimycin action is located. Because thyronamines exerted their effects at concentrations comparable to those found in hepatic tissue, it is conceivable that they can affect in vivo mitochondrial O(2) consumption and H(2)O(2) production acting as modulators of thyroid hormone action.

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Available from: Paola Venditti
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    • "binding site (affinity on the order of 50 nM), which prevents the interaction between the ATP synthase and its physiological inhibitor IF1, and a low affinity binding site (IC 50 = 28 μM), through which T1AM reduces enzyme activity. Consistent with these findings, T1AM has been reported to reduce oxygen consumption and increase hydrogen peroxide release in rat liver mitochondria (Venditti et al., 2011). At concentrations in the low micromolar range, T1AM interfered with monoamine transporters, namely norpinephrine transporter, dopamine transporter and vesicular monoamine transporter 2 (Snead et al., 2007). "
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    ABSTRACT: 3-iodothyronamine (T1AM) is an endogenous amine, that has been detected many rodent tissues, and in human blood. It has been hypothesized to derive from thyroid hormone metabolism, but this hypothesis still requires validation. T1AM is not a ligand for nuclear thyroid hormone receptors, but stimulates with nanomolar affinity trace amine-associated receptor 1 (TAAR1), a G protein-coupled membrane receptor. With a lower affinity it interacts with alpha2A adrenergic receptors. Additional targets are represented by apolipoprotein B100, mitochondrial ATP synthase, and membrane monoamine transporters, but the functional relevance of these interactions is still uncertain. Among the effects reported after administration of exogenous T1AM to experimental animals, metabolic and neurological responses deserve special attention, because they were obtained at low dosages, which increased endogenous tissue concentration by about one order of magnitude. Systemic T1AM administration favored fatty acid over glucose catabolism, increased ketogenesis and increased blood glucose. Similar responses were elicited by intracerebral infusion, which inhibited insulin secretion and stimulated glucagon secretion. However, T1AM administration increased ketogenesis and gluconeogenesis also in hepatic cell lines and in perfused liver preparations, providing evidence for a peripheral action, as well. In the central nervous system, T1AM behaved as a neuromodulator, affecting adrenergic and/or histaminergic neurons. Intracerebral T1AM administration favoured learning and memory, modulated sleep and feeding, and decreased the pain threshold. In conclusion T1AM should be considered as a component of thyroid hormone signalling and might play a significant physiological and/or pathophysiological role. T1AM analogues have already been synthetized and their therapeutical potential is currently under investigation.
    Full-text · Article · Oct 2014 · Frontiers in Physiology
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    • "The actions of the various ICs derived from the THs are not well known and seem to differ significantly. For instance, diiodothyronin (T2) produces metabolic effects similar to those of T3 [23] whereas thyronamines oppose its actions [24], at least at the mitochondrial level. This aspect of the thyroid physiology deserves further investigation. "
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    • "for complex II. Thus, in the presence of succinate, T1AM was able to produce minor effects on respiratory complexes (Venditti et al., 2011). The IC50 values (28.2 Ϯ 2.4 mM) indicate that the inhibitory potency of T1AM upon ATP synthase activity is similar to that of resveratrol (29.9 Ϯ 1.7 mM) (Figure 3A and B). "
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    ABSTRACT: 3-iodothyronamine (T1AM) is a metabolite of thyroid hormone acting as a signalling molecule via non-genomic effectors and can reach intracellular targets. Because of the importance of mitochondrial F(0) F(1) -ATP synthase as a drug target, here we evaluated interactions of T1AM with this enzyme. Kinetic analyses were performed on F(0) F(1) -ATP synthase in sub-mitochondrial particles and soluble F(1) -ATPase. Activity assays and immunodetection of the inhibitor protein IF(1) were used and combined with molecular docking analyses. Effects of T1AM on H9c2 cardiomyocytes were measured by in situ respirometric analysis. T1AM was a non-competitive inhibitor of F(0) F(1) -ATP synthase whose binding was mutually exclusive with that of the inhibitors IF(1) and aurovertin B. Both kinetic and docking analyses were consistent with two different binding sites for T1AM. At low nanomolar concentrations, T1AM bound to a high-affinity region most likely located within the IF(1) binding site, causing IF(1) release. At higher concentrations, T1AM bound to a low affinity-region probably located within the aurovertin binding cavity and inhibited enzyme activity. Low nanomolar concentrations of T1AM increased ADP-stimulated mitochondrial respiration in cardiomyocytes, indicating activation of F(0) F(1) -ATP synthase consistent with displacement of endogenous IF(1,) , reinforcing the in vitro results. Effects of T1AM on F(0) F(1) -ATP synthase were twofold: IF(1) displacement and enzyme inhibition. By targeting F(0) F(1) -ATP synthase within mitochondria, T1AM might affect cell bioenergetics with a positive effect on mitochondrial energy production at low, endogenous, concentrations. T1AM putative binding locations overlapping with IF(1) and aurovertin binding sites are described.
    Full-text · Article · Mar 2012 · British Journal of Pharmacology
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