Thyroid hormone action in mitochondria

Abstract

Triiodothyronine (T3) is considered a major regulator of mitochondrial activity. In this review, we show evidence of the existence of a direct T3 mitochondrial pathway, and try to clarify the respective importance of the nuclear and mitochondrial pathways for organelle activity. Numerous studies have reported short-term and delayed T3 stimulation of mitochondrial oxygen consumption. Convincing data indicate that an early influence occurs through an extra-nuclear mechanism insensitive to inhibitors of protein synthesis. Although it has been shown that diiodothyronines could actually be T3 mediators of this short-term influence, the detection of specific T3-binding sites, probably corresponding to a 28 kDa c-Erb A 1 protein of the inner membrane, also supports a direct T3 influence. The more delayed influence of thyroid hormone upon mitochondrial respiration probably results from mechanisms elicited at the nuclear level, including changes in phospholipid turnover and stimulation of uncoupling protein expression, leading to an increased inner membrane proton leak. However, the involvement of a direct mitochondrial T3 pathway leading to a rapid stimulation of mitochondrial protein synthesis has to be considered.Both pathways are obviously involved in the T3 stimulation of mitochondrial genome transcription. First, a 43 kDa c-Erb A 1 protein located in the mitochondrial matrix (p43), acting as a potent T3-dependent transcription factor of the mitochondrial genome, induces early stimulation of organelle transcription. In addition, T3 increases mitochondrial TFA expression, a mitochondrial transcription factor encoded by a nuclear gene. Similarly, the stimulation of mitochondriogenesis by thyroid hormone probably involves both pathways. In particular, the c-erb A gene simultaneously encodes a nuclear and a mitochondrial T3 receptor (p43), thus ensuring coordination of the expression of the mitochondrial genome and of nuclear genes encoding mitochondrial proteins.Recent studies concerning the physiological importance of the direct mitochondrial T3 pathway involving p43 led to the conclusion that it is not only involved in the regulation of fuel metabolism, but also in the regulation of cell differentiation. As the processes leading to or resulting from differentiation are energy-consuming, p43 coordination of metabolism and differentiation could be of significant importance in the regulation of development.

Uncoupling protein 1 expression in adipocytes derived from skeletal muscle fibro/adipogenic progenitors is under genetic and hormonal control

“…Importantly, in our study, this effect was dependent on a direct effect of T 3 on UCP1 levels rather than on FAP differentiation, as indicated by similar mRNA and protein levels of adipocyte markers and automated microscopy analysis of differentiation. We speculate that the increase in UCP1 gene and protein expression in FAPs differentiated in medium supplemented with T 3 could result at least partially from the stimulation of thyroid hormone response elements in the Ucp1 gene promoter,57 increased stability of Ucp1 mRNA,40 and/or enhanced mitochondriogenesis (extensively reviewed in Wrutniak‐Cabello et al 58…”

Effect of thyroid hormone on mitochondrial properties and oxidative stress in cells from patients with mtDNA defects

“…In addition, PGC-1␣ and Tfam are not the only possible routes for T 3 action on the mitochondria. T 3 has also been shown to directly regulate mtDNA transcription in cardiomyocytes by binding to TR-␣ isoforms that localize to the mitochondria and bind to thyroid response elements on mtDNA (50). Despite the lack of PGC-1␣ or Tfam elevations, there was an increase in COX activity for both control and patient cell lines with T 3 treatment.…”

Thyroid hormones in small ruminants: effects of endogenous, environmental and nutritional factors

“…Recently, several membrane transporters for cellular entry have been identified and they are now considered among the factors on which TH biological activity could depend (Hennemann et al, 2001;Friesema et al, 2005). As it is the case of steroid hormones some actions of TH are rapid and non-genomic (Davis et al, 2002;Hiroi et al, 2006) due to actions on mitochondria and cell Todini membranes on which binding proteins have been identified (Wrutniak-Cabello et al, 2001;Davis et al, 2005).…”

“…It is likely that during the first hours of life the thyroid gland can respond to other stimulating factors: small increases of plasma TH followed exogenous prolactin administration in neonatal lamb, but not in growing lambs and ewes (Peeters et al, 1992). Plasma rT3 levels during the first 48 h of life progressively decreased in suckling lambs, but increased in bottle-fed lambs (Cabello andWrutniak, 1986 and1990). Plasma T4 concentrations were higher in single lambs than in twins at birth (Assane and Sere, 1990).…”