Thyroid Hormone Action: The Mitochondrial Pathway

Sterling, Kenneth; Milch, Peter O.; Brenner, Milton A.; Lazarus, John H.

doi:10.1126/science.196334

Cited by 166 publications

(58 citation statements)

References 30 publications

(41 reference statements)

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…In addition, this effect was not abrogated by protein synthesis inhibitors (Sterling et al 1980). In vitro experiments also demonstrated that adding T3 to the incubation medium of isolated mitochondria from hypothyroid animals induced a similar influence within 2 min of the hormone being present (Sterling et al 1977, Thomas et al 1987. Moreover, Sterling & Brenner (1995) reported a stimulation of the mitochondrial carrier adenine nucleotide translocase (ANT) displaying the same features.…”

Section: Short-term Influencementioning

confidence: 52%

Thyroid hormone action in mitochondria

Wrutniak‐Cabello¹,

Casas²,

Cabello³

2001

Journal of Molecular Endocrinology

275

175

View full text Add to dashboard Cite

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.

show abstract

Section: Short-term Influencementioning

confidence: 52%

Thyroid hormone action in mitochondria

Wrutniak‐Cabello¹,

Casas²,

Cabello³

2001

Journal of Molecular Endocrinology

275

175

View full text Add to dashboard Cite

show abstract

“…The voluminous data that have resulted strongly suggest that the thyroid hormones exert a primary effect at the level of the cell nucleus (1)(2)(3)(4)(5), and perhaps the mitochondrion as well (6)(7)(8). In addition, evidence has grown that the thyroid hormones may also exert a direct effect that the level of the cell membrane.…”

Section: Introductionmentioning

confidence: 99%

Stimulation by Triiodothyronine of the In Vitro Uptake of Sugars by Rat Thymocytes

Segal¹,

Ingbar²

1979

J. Clin. Invest.

View full text Add to dashboard Cite

A B S T R A C T Studies were conducted to ascertain the in vitro effect of 3,5,3'-triiodothyronine (T3) on the accumulation of the glucose analogue, 2-deoxyglucose (2-DG), by thymocytes freshly isolated from weanling rats. At a concentration of 1 ,uM, T3 stimulated the 15-min uptake of 3H-2-DG after cells had been exposed to T3 for only 30 min. Significant stimulation of 2-DG accumulation was produced by 1 nM T3, with increasing stimulation at doses ranging up to 10 ,uM. T3 did not alter the fraction of accumulated 2-DG that was phosphorylated, and kinetic studies indicated that its effect was associated with a significant increase in the apparent Vmax of 2-DG accumulation, but not the apparent Km. T3 also enhanced the accumulation by thymocytes of the nonmetabolized glucose analogue, 3-0-methylglucose (3-0-MG), an effect that was evidently the result of an increase in 3-0-MG transport into the cell, because it was seen in cells incubated with 3H-3-O-MG for only 30 s. The proportionate increase in 2-DG accumulation produced by T3 was not altered by preincubating cells with concentrations of puromycin or cycloheximide sufficient to reduce [3H]-leucine incorporation by 95%, and T3 over a period of >2 h had no effect on [3H]leucine incorporation itself.These results indicate that T3 stimulates the uptake of sugars in rat thymocytes in vitro by an effect on their inward transport. The promptness of the effect and its failure to be inhibited during profound inhibition of protein synthesis further indicate that this effect of T3 is not mediated through a nuclear-dependent mechanism. Rather, the properties of this response, and of the increases in amino acid and 2-DG accumulation produced by T3 in other tissue preparations, strongly suggest that these effects of T3 are mediated at the level of cell membrane.

show abstract

“…Short-term effects of thyroid hormones include, among others: (1) an increase of oligomycin-sensitive oxygen consumption after addition of T 3 to the perfusion medium of liver from hypothyroid rats [4]; (2) a fall in the mitochondrial ATP/ADP ratio under the conditions of 1) [5] (3) a rapid stimulation of hepatocyte oxygen consumption in the presence of cycloheximide [6]; (4) a rapid increase of ATP synthesis within minutes [7]; and (5) an increase in the P/O ratio of liver mitochondria isolated 15 min after injection of T 3 into thyroidectomized rats [8].…”

Section: Introductionmentioning

confidence: 99%

Interaction of diiodothyronines with isolated cytochromec oxidase

et al. 1994

View full text Add to dashboard Cite

Diiodothyronines (3,3'-T2 and 3,5-T2) stimulate the activity of isolated cytochrome c oxidase (COX) from bovine heart mitochondria. Maximal stimulation of activity (about 50%) is obtained with 3,3'-T2 at pH 6.4 and with 3,5-T2 at pH 7.4. In contrast, 3,5,3'-triiodothyronine (TO exhibited no or little stimulation of COX activity. Binding of the hormones to COX leads to conformational changes as shown by modified visible spectra of the oxidized enzyme. It is suggested that 'short-term' effects of thyroid hormones on mitochondrial respiration are at least partly due to the allosteric interaction of diiodothyronines with the COX complex.

show abstract

Thyroid Hormone Action: The Mitochondrial Pathway

Cited by 166 publications

References 30 publications

Thyroid hormone action in mitochondria

Thyroid hormone action in mitochondria

Stimulation by Triiodothyronine of the In Vitro Uptake of Sugars by Rat Thymocytes

Interaction of diiodothyronines with isolated cytochromec oxidase

Contact Info

Product

Resources

About