Thyroid hormone action in mitochondria

Triiodothyronine (T3) is considered a major regulator of mitochondrial acti vity. In this review, we show evidence of the existence of a direct T3 mito chondrial pathway, and try to clarify the respective importance of the nucl ear and mitochondrial pathways for organelle activity. Numerous studies hav e reported short-term and delayed T3 stimulation of mitochondrial oxygen co nsumption. Convincing data. indicate that an early influence occurs through an extra-nuclear mechanism insensitive to inhibitors of protein synthesis. Although it has been shown that diiodothyronines could actually be T3 medi ators of this short-term influence, the detection of specific T3-binding si tes, probably corresponding to a 28 kDa c-Erb A alpha1 protein of the inner membrane, also supports a direct T3 influence. The more delayed influence of thyroid hormone upon mitochondrial respiration probably results from mec hanisms elicited at the nuclear level, including changes in phospholipid tu rnover and stimulation of uncoupling protein expression, leading to an incr eased inner membrane proton leak. However, the involvement of a direct mito chondrial T3 pathway leading to a rapid stimulation of mitochondrial protei n synthesis has to be considered. Both pathways are obviously involved in the T3 stimulation of mitochondrial genome transcription. First, a 43 kDa c-Erb A alpha1 protein located in th e mitochondrial matrix (p43), acting as a potent T3-dependent transcription factor of the mitochondrial genome, induces early stimulation of organelle transcription. In addition, T3 increases mitochondrial TFA expression, a m itochondrial transcription factor encoded by a nuclear gene. Similarly, the stimulation of mitochondriogenesis by thyroid hormone probably involves bo th pathways. In particular, the c-erb A alpha gene simultaneously encodes a nuclear and a mitochondrial T3 receptor (p43), thus ensuring coordination of the expression of the mitochondrial genome and of nuclear genes encoding mitochondrial proteins. Recent studies concerning the physiological importance of the direct mitoch ondrial T3 pathway involving p43 led to the conclusion that it is not only involved in the regulation of fuel metabolism, but also in the regulation o f cell differentiation. As the processes leading to or resulting from diffe rentiation are energy-consuming, p43 coordination of metabolism and differe ntiation could be of significant importance in the regulation of developmen t.