Studies on the rapid stimulation of mitochondrial respiration by thyroid hormones

Abstract

Injection of L-3,5-diiodothyronine (T2) into rats made hypothyroid by 6-n-propyl-2-thiouracil (PTU) increased the respiration rates of subsequently isolated liver mitochondria; this stimulation of respiration by T2 occurred in the presence of cycloheximide and is therefore independent of protein synthesis on cytoplasmic ribosomes. Injection of T3 into PTU-treated rats had a lesser effect than T2 on the respiration rates of subsequently isolated mitochondria; as PTU is an inhibitor of 5\m='\-iodothyronine deiodinases, which convert T3 into T2 in vivo, the rapid stimulation of mitochondrial respiration by T3, which has been shown in a range of systems, may not be due directly to T3 itself, but may be mediated by its deiodination product T2. Injection of T2, or T3, into hypothyroid or euthyroid rats had no effect on the percentage activity of mitochondrial pyruvate hydrogenase assayed 30 min later. The amount of active pyruvate dehydrogenase is regulated by changes in mitochondrial calcium concentration and matrix ATP/ADP ratio; therefore these parameters are not persistently affected by treatment with T3 or T2. In addition, the total amount of pyruvate dehydrogenase present was the same in euthyroid and hypothyroid rats, indicating that the expression of this enzyme is not stringently controlled by thyroid hormone status.

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

“…Triiodothyronine, the generally accepted active form of thyroid hormones, may alter the concentration of individual enzymes or may influence, directly or indirectly, their kinetic properties (for review see Brand and Murphy [21]). 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].…”

“…In effect, diiodothyronines either could influence other parameters or could not easily enter into the cells when injected in vivo. In addition, it has been recently demonstrated that diiodothyronines, when administered in vivo, stimulate liver cell metabolism [1,2,5].…”

3,5-Diiodo- l -thyronine and 3,5,3′-triiodo- l -thyronine both improve the cold tolerance of hypothyroid rats, but possibly via different mechanisms

“…Our previous studies showing the presence of specific binding sites for 3,5-T2 in rat liver mitochondria [9] and direct interaction of 3,5-T2 with isolated CO complexes [10] are consistent with this notion. In addition, O' Reilly and Murphy [23] have reported that the stimulatory effect exerted by 3,5-T2 on rat liver mitochondrial respiration is independent of the protein synthesis.…”

“…Recent studies, in fact, show that T2s may be calorigenic when injected into hypothyroid rats [19] and may stimulate mitochondrial activity [17,18,23] and the metabolic activity of several tissues and cells [16,18,19]. These results lead us to hypothesise that T2s, through such mechanisms, also may be involved in the regulation of energy metabolism in physiological situations requiring extra energy expenditure, such as cold exposure [19].…”

Interaction of diiodothyronines with isolated cytochromec oxidase

“…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].…”