Kinetics of internalization and subcellular binding sites for T<sub>3</sub> in mouse liver

Morel, G.; Ricard‐Blum, Sylvie; Ardail, Dominique

doi:10.1016/0248-4900(96)84781-2

Cited by 23 publications

(11 citation statements)

References 40 publications

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“…These data indicate that, like mt-TFA, p43 induced a strong increase in the levels of mitochondrial precursor transcripts in the presence of exogenous T3. A reduced p43 influence was observed in the absence of exogenous T3, in agreement with the fact that mitochondria are a major compartment of T3 accumulation in the cell (32,49). In addition, all of the precursor transcripts induced by p43 or mt-TFA were also detected in Northern blots performed with other mitochondrial probes (Cytb, ND 5, ND 4, ATPase 6/COX II, ND 6L, COX I, ND 2, or ND 1; Fig.…”

Section: Resultssupporting

confidence: 71%

A Variant Form of the Nuclear Triiodothyronine Receptor c-ErbAα1 Plays a Direct Role in Regulation of Mitochondrial RNA Synthesis

Casas

Rochard

Rodier

et al. 1999

Molecular and Cellular Biology

198

156

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In earlier research, we identified a 43-kDa c-ErbAalpha1 protein (p43) in the mitochondrial matrix of rat liver. In the present work, binding experiments indicate that p43 displays an affinity for triiodothyronine (T3) similar to that of the T3 nuclear receptor. Using in organello import experiments, we found that p43 is targeted to the organelle by an unusual process similar to that previously reported for MTF1, a yeast mitochondrial transcription factor. DNA-binding experiments demonstrated that p43 specifically binds to four mitochondrial DNA sequences with a high similarity to nuclear T3 response elements (mt-T3REs). Using in organello transcription experiments, we observed that p43 increases the levels of both precursor and mature mitochondrial transcripts and the ratio of mRNA to rRNA in a T3-dependent manner. These events lead to stimulation of mitochondrial protein synthesis. In transient-transfection assays with reporter genes driven by the mitochondrial D loop or two mt-T3REs located in the D loop, p43 stimulated reporter gene activity only in the presence of T3. All these effects were abolished by deletion of the DNA-binding domain of p43. Finally, p43 overexpression in QM7 cells increased the levels of mitochondrial mRNAs, thus indicating that the in organello influence of p43 was physiologically relevant. These data reveal a novel hormonal pathway functioning within the mitochondrion, involving a truncated form of a nuclear receptor acting as a potent mitochondrial T3-dependent transcription factor.

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Section: Resultssupporting

confidence: 71%

A Variant Form of the Nuclear Triiodothyronine Receptor c-ErbAα1 Plays a Direct Role in Regulation of Mitochondrial RNA Synthesis

Casas

Rochard

Rodier

et al. 1999

Molecular and Cellular Biology

198

156

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“…Rapidity, refractoriness to inhibitors of protein synthesis, and occurrence in the absence of nuclei ruled out the involvement of the T3 genomic pathway. Parallel to this, several studies have demonstrated that the mitochondrion is a major compartment of T3 accumulation in the cell (Palacios-Romero & Mowbray 1979, Sterling et al 1984b, Hashizume et al 1986, Morel et al 1996. These data led to the proposition that ANT was a major T3 target involved in the short-term influence of the hormone on the organelle.…”

Section: Short-term Influencementioning

confidence: 94%

Thyroid hormone action in mitochondria

Wrutniak‐Cabello¹,

Casas²,

Cabello³

2001

Journal of Molecular Endocrinology

275

175

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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.

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“…Further, a specific mitochondrial receptor for T3 has still not been identified. Quite recently, however, the existence of specific mitochondrial binding sites for T3 has received additional confirmation from the work of Morel et al [40] and Wrutniak et al [36].…”

Section: Non‐nuclear Action Of Iodothyronines: the Direct Mitochondrimentioning

confidence: 97%

“…Morel et al [40] studied the kinetics of the internalization and specific subcellular binding of T3 in mouse liver both in vivo and in vitro. These authors showed by quantitative electron microscopy autoradiography that, after the injection of radiolabelled T3, specific binding was displayed by five cell compartments (including mitochondria).…”

Section: Non‐nuclear Action Of Iodothyronines: the Direct Mitochondrimentioning

confidence: 99%

Action of thyroid hormones at the cellular level: the mitochondrial target

1999

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Thyroid hormones exert profound effects on the energy metabolism. An inspection of the early and more recent literature shows that several targets at the cellular level have been identified. Since their effects on the nuclear signalling pathway have already been well-defined and extensively reviewed, this article focuses on the regulation of mitochondrial activity by thyroid hormones. Mitochondria, by virtue of their biochemical functions, are a natural candidate as a direct target for the calorigenic effects of thyroid hormones. To judge from results coming from various laboratories, it is quite conceivable that mitochondrial activities are regulated both directly and indirectly. Not only triiodo-L-thyronine, but also diiodothyronines are active in regulating the energy metabolism. They influence the resting metabolism in rats with 3,5-diiodo-Lthyronine seeming to show a clearer effect.z 1999 Federation of European Biochemical Societies.

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Kinetics of internalization and subcellular binding sites for T₃ in mouse liver

Cited by 23 publications

References 40 publications

A Variant Form of the Nuclear Triiodothyronine Receptor c-ErbAα1 Plays a Direct Role in Regulation of Mitochondrial RNA Synthesis

A Variant Form of the Nuclear Triiodothyronine Receptor c-ErbAα1 Plays a Direct Role in Regulation of Mitochondrial RNA Synthesis

Thyroid hormone action in mitochondria

Action of thyroid hormones at the cellular level: the mitochondrial target

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Kinetics of internalization and subcellular binding sites for T3 in mouse liver

Cited by 23 publications

References 40 publications

A Variant Form of the Nuclear Triiodothyronine Receptor c-ErbAα1 Plays a Direct Role in Regulation of Mitochondrial RNA Synthesis

A Variant Form of the Nuclear Triiodothyronine Receptor c-ErbAα1 Plays a Direct Role in Regulation of Mitochondrial RNA Synthesis

Thyroid hormone action in mitochondria

Action of thyroid hormones at the cellular level: the mitochondrial target

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Kinetics of internalization and subcellular binding sites for T₃ in mouse liver