A 43-kDa protein related to c-Erb A alpha 1 is located in the mitochondrial matrix of rat liver.

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.

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

https://febs.onlinelibrary.wiley.com/doi/pdf/10.1016/S0014-5793%2899%2900642-0

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

https://febs.onlinelibrary.wiley.com/doi/pdf/10.1016/S0014-5793%2803%2900320-X

Thyroid hormone and uncoupling proteins

The contribution of the leak of protons across the mitochondrial inner membrane to standard metabolic rate.

1
Chronic treatment of thyroidectomized rats with physiological doses of triiodothyronine leads to a significant increase in the incorporation of [3H]UTP into RNA by isolated rat liver mitochondria after the 4th day of treatment.

2
The increased activity of mitochondrial RNA polymerase is followed by a net increase in the RNA content of organelles which can be observed after the 5th day of chronic treatment.

3
Single injection of triiodothyronine at a dose of 250 μg/kg body wt also causes great stimulation of mitochondrial RNA synthesis which increases three-fold after 40 h.

4
At the same DNA/RNA ratio, RNA labelled in vitro with [3H]UTP from liver mitochondria of thyroidectomized animals hybridizes with mitochondrial DNA less efficiently than the newly synthesized RNA from liver mitochondria of animals treated for 10 days with 5 μg/100 g body wt of the hormone.

5
Hybridization-competition experiments with unlabelled RNA extracted from mitochondria of treated and untreated animals seem to suggest that a change in the transcription of mitochondrial DNA under the influence of the hormone occurs also in vivo.

https://febs.onlinelibrary.wiley.com/doi/pdf/10.1111/j.1432-1033.1972.tb02108.x

Triiodothyronine action on RNA synthesis in rat-liver mitochondria.

The authors have determined the liver mitochondrial population (number of mitochondria/nucleus) in young rats, which has been thyroidectomized (
 
$$\bar T$$

 ) or thyroidectomized and subsequently treated with triiodothyronine (T3). They have observed that thyroidectomy decreased such a population to 72.3% with respect to the normal one, while the T3 administration (at the dose of 10 μg/100 g body weight every second day, from day 50 to day 60 of age) restored the mitochondria number to 81.8% of normal ones. The average levels of proteins per mitochondrion were 8.90×10−13 g in the liver of normal 60-day-old rats. This content was doubled in
 
$$\bar T$$

 rats of the same age while the levels of nucleic acids or the nucleic acid polymerase activities per mitochondrion were enhanced, notwithstanding that the specific values (referred to mg mitochondrial protein) decreased. The T3 administration severely lowered the content of protein per mitochondrion, and this may indicate that thyroid hormones control the normal assemblage of mitochondrial protein.

Modification of nucleic acid levels per mitochondrion induced by thyroidectomy or triiodothyronine administration.

The authors have determined the serum thyroid hormone levels [total and free triiodothyronine (T3), thyroxine (T4)], the liver T3 content, the mitochondrial α-glycerophosphate dehydrogenase activity (α-GPDH) and the number of mitochondria per cell in the rat from birth to old age. The serum levels of both thyroid hormones are modified with maturation and ageing in an essentially similar way: they increase from low values at birth to remarkably high values around 12 days, and then remain costant. The T3 liver content firstly increases (from birth to 14 days of life) and then maintains constant values. During the first two postnatal weeks, therefore, free serum T3 and liver T3 display a similar behavior. The α-GPDH activity of liver mitochondria was found constant from birth to old age. This might suggest either that the control of the α-GPDH activity is, at birth, under complex hormonal control, or that the nuclear receptors associated with the α-GPDH genes are precociously synthesized. The number of mitochondria per cell, at birth, is half the adult values, strongly increasing in number at weaning and remaining constant afterwards. The effect of thyroid hormones on the mitochondrial population during maturation, when low levels of serum T3 and T4 occur naturally, appears to be quite different from that induced experimentally by thyroidectomy.

Teodoro De Leo

Papers

Triiodothyronine action on RNA synthesis in rat-liver mitochondria.

Modification of nucleic acid levels per mitochondrion induced by thyroidectomy or triiodothyronine administration.

Thyroid state and mitochondrial population during maturation and ageing

Effects of testosterone and of tri-iodothyronine on the levels of mitochondrial DNA and RNA from rat liver.

Biosynthesis of cholesterol from long-chain fatty acids in cell-free systems from rat liver