La voie d'action mitochondriale directe de la triiodothyronine: mythe ou réalité ?

Abstract

La caractérisation des récepteurs nucléaires de la triiodothyronine (T3) en 1986, a fourni de précieux outils moléculaires pour l’étude de l’action génomique de cette hormone. Tout naturellement, la quasi-totalité des travaux concernant les mécanismes d’action de la T3 se sont focalisés sur cette action nucléaire. Néanmoins, plusieurs modes d’action intracellulaires de la triiodothyronine ont été proposés et font toujours l’objet d’une intense controverse. La voie d’action nucléaire de la T3 est-elle exclusive ? existe-t-il des voies d’action membranaire et mitochondriale de la T3? Nos données nouvelles, associées à une analyse objective des divers résultats expérimentaux permettent aujourd’hui d’apporter un éclairage nouveau sur la réalité de la voie d’action mitochondriale de la triiodothyronine.

Besides the well established triiodothyronine (T3) nuclear pathway, direct influences of this hormone upon cell membrane and mitochondria have been proposed. However, although a T3 stimulation of calcium influx and cAMP production have been reported, an hypothetical T3 membrane receptor remains to be identified. Numerous data underline that T3 exerts short and long-term effects upon mitochrondria. In particular, hormonal stimulation of oxygen consumption, ATP synthesis and mitochondrial translocator activity have been reported. These influences are detected with a short latency period, in in vivo experiments as well as on isolated mitochondria, and are not affected by protein synthesis inhibitors. Therefore, they are not mediated by T3 nuclear receptors. In addition, a long-term effect upon mitochondrial biogenesis is well established. The short-term stimulation of mitochondrial activity by T3 is linked to an increase in the inner membrane area and acute changes in its phospholipid composition. This phenomenon induces in turn an increase in mitochondrial carriers and enzymes activities and a rise in inner membrane proton leak. In addition, T3 also stimulates mitochondrial gene expression. Several mechanisms have been proposed to explain the T3 mitochondrial influence. An increase in the mitochondrial calcium pool, a possible ADP-ribosylation of an inner membrane protein, or an induction of cytochrome-oxidase allosteric changes have been proposed to be involved in the short-term influence of T3. Moreover, evidences suggesting that the nuclear pathway is involved in long-term influences are provided. Lastly, the identification of a c-ErbA-related protein in the mitochondrial matrix, inducing strong changes in mitochondrial activity, clearly established the occurrence of a direct T3 mitochondrial pathway. Over all, it appears that T3 influences mitochondrial activity by a number of different mechanisms initiated inside and outside the organelle.