Stimulation of Mitochondrial Adenosine Diphosphate Uptake by Thyroid Hormones

Abstract

Thyroid hormone administered in vivo increased carrier-mediated (atractyloside-sensitive) ADP uptake by rat liver mitochondria. 3 Days after a single large dose of triiodothyronine (20 ;g/100 g of body weight), mitochondrial uptake of ADP measured at 60 was 2.35 4 0.17 nmol/min per mg of protein, compared with an uptake of 1.81 i 0.19 nmol/min per mg of protein in mitochondria from untreated rats (P < 0.025). Cyanide (1.33 mM) had no effect on ADP uptake by mitochondria from either untreated or triiodothyronine-treated animals. Uptake of ADP by mitochondria from thyroidectomized rats treated with thyroxine for 7 days was 2.89 4 0.40 nmol/min per mg in mitochondria from thyrotoxic rats (20 ug of thyroxine per 100 g per day) and 1.98 -0.22 nmol/min per mg in mitochondria from euthyroid rats (2 ug of thyroxine per 100 g per day) (P < 0.025). Mitochondria from both untreated and thyroid hormone-treated rats displayed a highly significant linear correlation between ADP uptake and ADP-dependent (i.e., state 3 minus state 4) oxygen consumption. There was, however, no difference in respiratory control ratios between mitochondria from euthyroid and thyrotoxic animals. Administration of dinitrophenol (2 mg/100 g) also stimulated carrier-mediated ADP uptake, but respiratory control of mitochondria from dinitrophenol-treated animals was virtually abolished. Triiodothyronine in vitro, at concentrations of 100 and 0.1 nM, appeared to inhibit rather than stimulate the uptake of mitochondrial ADP. The relationship between these observations and the clinical manifestations of thyrotoxicosis is discussed from the point of view of the possible effects of increased mitochondrial ADP transport on oxidative phosphorylation and adenosyl nucleotide metabolism.It has long been known that an increase in metabolic rate follows administration of a sufficient dose of thyroid hormone. Animals treated with large doses of thyroxine manifest an increased rate of oxygen consumption, a rise in body temperature, and a loss in weight, all consequent to an increase in the rate of oxidation of substrate (1, 2). Since most substrate oxidation takes place in mitochondria, many studies on the mechanism of action of thyroid hormone have involved these organelles. These studies have shown, for example, that * To whom to address correspondence. thyroid hormone increases the rate of mitochondrial oxidation of succinate, glutamate, ,-hydroxybutyrate, and isocitrate (3); the activity of the electron transport chain is increased without an increase in the concentrations of the chain components (4); and there is an increase in the activity of membrane-bound a-glycerophosphate dehydrogenase (5).In addition, thyroid hormone affects mitochondrial swelling (6, 7) and respiratory control (8), but these effects are only observed with rather large doses of hormone.The mitochondrion is composed of an outer membrane, an inner membrane, and two spaces: the intermembrane space, which lies between the membranes, and the matrix, which is enclosed within the inner me...

Direct thyroid hormone signalling via ADP‐ribosylation controls mitochondrial nucleotide transport and membrane leakiness by changing the conformation of the adenine nucleotide transporter

“…We showed that thyroid deficiency led to an increase in the apparent Km of the ANT of rat liver mitochondria from the euthyroid value of 2.8 ~M to 6.3 p.M and that this was returned to normal 15 rain after a near-physiological intravenous dose of T3 [5]. Increases in the ANT transport rate at longer times after thyroid hormone administration reported by others [25,26] probably reflect an increased number of transporters in the membranes. The data shown in Table 1 demonstrate that, in agreement with these earlier findings, the highly significant decrease in the transport rate in hypothyroid preparations observed at a concentration of ADP near to the Km is not detectable at a much higher concentration.…”

Regulation of adenine nucleotide translocase and glycerol 3-phosphate dehydrogenase expression by thyroid hormones in different rat tissues

“…It has been observed that the ATP\ADP exchange is enhanced in liver mitochondria isolated from hyperthyroid rats and diminished in the hypothyroid state [5]. However, there are conflicting data as to whether this alteration in ADP\ATP exchange is due to corresponding alterations in gene expression.…”

“…the FAD-linked glycerol 3-phosphate dehydrogenase (mGPDH) are targets of thyroid hormone action [5,6].…”

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

“…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.…”