Rapid Effect of Triiodothyronine on the Mitochondrial Pathway in Rat Liver in Vivo

Sterling, Kenneth; Brenner, Milton A.; Sato, Toshiro

doi:10.1126/science.7423197

Cited by 120 publications

(65 citation statements)

References 20 publications

Supporting

Mentioning

Contrasting

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.…”

Section: Short-term Influencementioning

confidence: 61%

“…Several studies have reported that T3 injection in hypothyroid rats increases oxygen consumption and oxidative phosphorylations measured in isolated liver mitochondria collected less than 30 min after hormone administration (PalaciosRomero & Mowbray 1979, Sterling et al 1980). In addition, this effect was not abrogated by protein synthesis inhibitors (Sterling et al 1980).…”

Section: Short-term Influencementioning

confidence: 99%

See 1 more Smart Citation

Thyroid hormone action in mitochondria

Wrutniak‐Cabello¹,

Casas²,

Cabello³

2001

Journal of Molecular Endocrinology

268

169

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: 61%

Section: Short-term Influencementioning

confidence: 99%

Thyroid hormone action in mitochondria

Wrutniak‐Cabello¹,

Casas²,

Cabello³

2001

Journal of Molecular Endocrinology

268

169

View full text Add to dashboard Cite

show abstract

“…The second alternative is supported by earlier (42,43) and recent (1,48) reports that have proposed the existence of T 3 (3,3,5-triiodo-L-thyronine) binding proteins in mitochondria, which could interact with cis elements of mtDNA (7,48). However, the lack of experimental evidence showing thyroid hormone-mediated transcription regulation in the absence of nuclear gene expression prevents any definitive conclusion about whether direct regulation of mtDNA transcription by this hormone occurs (38).…”

mentioning

confidence: 57%

Direct Regulation of Mitochondrial RNA Synthesis by Thyroid Hormone

Enríquez

Fernández‐Silva

Garrido-Pérez

et al. 1999

Molecular and Cellular Biology

143

View full text Add to dashboard Cite

We have analyzed the influence of in vivo treatment and in vitro addition of thyroid hormone on in organello mitochondrial DNA (mtDNA) transcription and, in parallel, on the in organello footprinting patterns at the mtDNA regions involved in the regulation of transcription. We found that thyroid hormone modulates mitochondrial RNA levels and the mRNA/rRNA ratio by influencing the transcriptional rate. In addition, we found conspicuous differences between the mtDNA dimethyl sulfate footprinting patterns of mitochondria derived from euthyroid and hypothyroid rats at the transcription initiation sites but not at the mitochondrial transcription termination factor (mTERF) binding region. Furthermore, direct addition of thyroid hormone to the incubation medium of mitochondria isolated from hypothyroid rats restored the mRNA/rRNA ratio found in euthyroid rats as well as the mtDNA footprinting patterns at the transcription initiation area. Therefore, we conclude that the regulatory effect of thyroid hormone on mitochondrial transcription is partially exerted by a direct influence of the hormone on the mitochondrial transcription machinery. Particularly, the influence on the mRNA/rRNA ratio is achieved by selective modulation of the alternative H-strand transcription initiation sites and does not require the previous activation of nuclear genes. These results provide the first functional demonstration that regulatory signals, such as thyroid hormone, that modify the expression of nuclear genes can also act as primary signals for the transcriptional apparatus of mitochondria.Thyroid hormone regulates the expression of key nucleus encoded mitochondrial genes (23,37,38,47) and the steadystate concentration of all mitochondrial DNA (mtDNA)-encoded mRNAs (mt-mRNAs) (15-17, 32, 44). In rat liver, changes in mt-mRNA levels in response to in vivo treatment with thyroid hormones were well correlated with amounts of the corresponding polypeptides, while mtDNA copy number remained unmodified (33,47). Based on these observations, transcriptional control has been tentatively proposed as the main mechanism to explain the thyroid hormone effect on mt-mRNA steady-state levels and protein synthesis (33-36).Two alternative potential mechanisms for the regulation of mtDNA transcription by thyroid hormone have been suggested: through activation of mitochondrial transcription factor A (mtTFA) expression (18, 45), or by a direct action of the hormone through mitochondrial receptors (48). The second alternative is supported by earlier (42, 43) and recent (1, 48) reports that have proposed the existence of T 3 (3,3,5-triiodo-L-thyronine) binding proteins in mitochondria, which could interact with cis elements of mtDNA (7, 48). However, the lack of experimental evidence showing thyroid hormone-mediated transcription regulation in the absence of nuclear gene expression prevents any definitive conclusion about whether direct regulation of mtDNA transcription by this hormone occurs (38). Presently it is more generally believed that this transcripti...

show abstract

“…The precise mechanism for immediate T 3 action on liver mitochondria ANT remains controversial, but some studies implicate T 3 allosteric modification of an ADP-ribosyl transferase, which covalently modifies ANT, as opposed to direct T 3 binding to ANT (27). Importantly, T 3 did not accelerate ANT exchange in similarly prepared testes or spleen mitochondria, implying organ specificity due to differences in isoform distribution (50). Previous investigators did not evaluate mitochondria from cardiac or skeletal muscle, prompting our detailed analyses performed both in vivo and in vitro.…”

Section: Discussionmentioning

confidence: 99%

Direct action of T₃on phosphorylation potential in the sheep heart in vivo

Portman

Qian

Krueger

et al. 2005

American Journal of Physiology-Heart and Circulatory Physiology

View full text Add to dashboard Cite

Thyroid acting through ligand binding to nuclear receptors modifies myocardial respiratory kinetics and oxidative phosphorylation in the heart. Direct nongenomic action of thyroid hormone on high-energy phosphate concentrations and respiratory kinetics has never been proven in vivo but might be responsible for observed changes in oxygen utilization efficiency immediately after triiodothyronine (T3) administration. We tested the hypothesis that T3 directly and rapidly modifies myocardial high-energy phosphate concentrations and phosphorylation potential in vivo. Anesthetized sheep (age 28 -40 days) thyroidectomized shortly after birth (Thy) and euthyroid age-matched controls (Con) underwent median sternotomy and received T3 infusion (0.8 g/kg), followed by epinephrine infusion to increase myocardial oxygen consumption (MV O2).31 P magnetic resonance spectra were monitored via a surface coil over the left ventricle. T3 increased phosphocreatine (PCr)/ATP and decreased ADP in Thy animals without causing a change in MV O2. T3 produced no changes in high-energy phosphates in Con animals. T3 did not modify the PCr/ATP or ADP response to epinephrine and elevation in MV O2 in either group. Cardiac mitochondria isolated from Thy and Con animals showed no change in respiratory rate or ADP/ATP exchange efficiency after T3 incubation. T3 infusion in a hypothyroid state decreases ADP concentration, thereby altering the equilibrium between phosphorylation potential and myocardial respiratory rate. These T3-induced effects are not due to changes in ADP/ATP exchange efficiency through action at the adenine nucleotide translocator but may be due to T3 mediation of substrate utilization, confirmed in other models. adenine nucleotide translocator; myocardial energy metabolism; substrate oxidation THYROID HORMONE REGULATES myocardial metabolism at the transcriptional level through binding to nuclear receptors. Ligand-dependent binding of these receptors to thyroid receptor elements controls transcription of various target genes involved in contractile and metabolic processes (5, 16). Although these nuclear receptor-mediated processes have been investigated to some extent, thyroid hormone as its active component, triiodothyronine (T 3 ), also regulates cellular processes through direct binding to membranes or enzymes (2).The direct or nongenomic actions of T 3 on cardiac energy metabolism and high-energy phosphate kinetics remain somewhat obscure. In previous studies, we (20) demonstrated that T 3 directly regulates myocardial substrate oxidation in isolated, perfused hearts. The relationship between substrate oxidation and phosphorylation potential has been established in several cardiac models (23,43). An apparent equilibrium exists between mitochondrial NADH/NAD and cytosolic phosphorylation potential. Accordingly, we considered that T 3 could also elevate phosphorylation potential in vivo. Prior studies in sheep in vivo implicate the adenine nucleotide translocator (ANT), which facilitates ADP/ATP exchange across the mitochondri...

show abstract

Rapid Effect of Triiodothyronine on the Mitochondrial Pathway in Rat Liver in Vivo

Cited by 120 publications

References 20 publications

Thyroid hormone action in mitochondria

Thyroid hormone action in mitochondria

Direct Regulation of Mitochondrial RNA Synthesis by Thyroid Hormone

Direct action of T₃on phosphorylation potential in the sheep heart in vivo

Contact Info

Product

Resources

About

Rapid Effect of Triiodothyronine on the Mitochondrial Pathway in Rat Liver in Vivo

Cited by 120 publications

References 20 publications

Thyroid hormone action in mitochondria

Thyroid hormone action in mitochondria

Direct Regulation of Mitochondrial RNA Synthesis by Thyroid Hormone

Direct action of T3on phosphorylation potential in the sheep heart in vivo

Contact Info

Product

Resources

About

Direct action of T₃on phosphorylation potential in the sheep heart in vivo