Effect of 3,3′-di-iodothyronine and 3,5-di-iodothyronine on rat liver mitochondria

Abstract

In the present study we report that 3,3',5-tri-iodothyronine (T3) as well as two iodothyronines (3,5-di-iodothyronine (3,5-T2) and 3,3'-di-iodothyronine (3,3'-T2)) significantly influence rat liver mitochondrial activity. Liver oxidative capacity (measured as cytochrome oxidase activity/g wet tissue) in hypothyroid compared with normal rats was significantly reduced (21%, P > 0.01) and the administration of T3 and both iodothyronines restored normal values. At the mitochondrial level, treatment with T3 stimulated respiratory activity (state 4 and state 3) and did not influence cytochrome oxidase activity. On the other hand, both the mitochondrial respiratory rate and specific cytochrome oxidase activity significantly increased in hypothyroid animals after treatment with 3,3'-T2 or 3,5-T2 (about 50 and 40% respectively). The actions of both iodothyronines were rapid and evident by 1 h after the injection. The hepatic mitochondrial protein content which decreased in hypothyroid rats (9.6 mg/g liver compared with 14.1 in normal controls, P < 0.05) was restored by T3 injection, while neither T2 was able to restore it. Our results suggest that T3 and both iodothyronines have different mechanisms of action. T3 acts on both mitochondrial mass and activity; the action on mitochondrial activity was not exerted at the cytochrome oxidase complex level. The action of the iodothyronines, on the other hand, is exerted directly on the cytochrome oxidase complex without any noticeable action on the mitochondrial mass.

Interaction of diiodothyronines with isolated cytochromec oxidase

“…Diiodothyronines either could have different effects, or could not reach their intracellular targets when injected into animals. As previously hypothesized [15,16], T 3 could be responsible for long-lasting action of thyroid hormones, whereas diiodothyronines could be involved in rapid energetic adjustment to an altered physiological state, such as cold exposure, overfeeding etc.…”

“…Concerning the lack of diiodothyronines effects on basal metabolic rate, after their administration in vivo [15,25], it is possible that plasma membranes are not permeable to diiodothyronines and that they are only formed within cells from Ts. Only after chronic treatment of hypothyroid animals, it is possible to show an effect of diiodothyronines in some tissues such as the liver, which could be more permeable to diiodothyronines [12,13], but this has only little effect on basal metabolic rate (= 10-20% stimulation) [15,16].…”

“…Recently, however, several authors described 'short-term' effects of diiodothyronines (3,3'-T2 and 3,5-T2) on mitochondrial respiration [15][16][17][18][19][20]. In a previous study we showed a rapid in vitro stimulation of cytochrome c oxidase (COX) activity in rat liver mitochondria by 3,3'-T2 and 3,5-T2 and suggested that diidothyronines alter the kinetic properties of the COX complex by interaction with nuclear-coded (non-catalytic) subunits of COX [17].…”

Specific binding sites for 3,3′‐diiodo‐l‐thyronine (3,3′‐T2) in rat liver mitochondria

“…Recently, as mentioned before, several reports dealing with the action of iodothyronines at the cellular level, have shown that two diiodothyronines (3,3'-T2 and 3,5-TE) are the thyroid hormone analogues which are most effective at the cellular level [1][2][3][4][5][6]. In previous studies we hypothesized that T3 could be responsible for the nuclear and long-term actions of thyroid hormones and diiodothyronines for the direct mitochondrial short-term actions [1,2]. This hypothesis presupposes the presence of specific binding sites for diiodothyronines in mitochondria.…”

“…In fact, in spite of several reports showing rapid effects of triiodothyronine (T3) on mitochondria, the occurrence and the physiological significance of these effects is a long standing controversial issue of thyroid hormone action. In recent years, however, several reports have shown that two diiodothyronines (3,3'-T2 and 3,5-T2), under certain conditions, are the only iodothyronines which rapidly stimulate in vivo and in vitro mitochondrial respiration or cytochrome oxidase (COX) activity [1][2][3][4][5][6]. At the moment, the physiological significance of these effects is not clear and no insight into the mechanism by which diiodothyronines stimulate mitochondrial energy metabolism is available.…”