Figure 1. Schematic representation of the TH‐dependent nucleus‐mitochondrion regulation of mitochondrial functions. Trough active transport or passive diffusion, TH (T4/T3) move from outside the plasma membrane into the cytoplasm approaching the extranuclear as well as the extramitochondrial space. Moreover, TH can bind to surface receptor such as integrin αvb3 receptor. In the cytoplasm, several events can occur, among which deiodination (conversion of T4 into T3 by D1 or D2 action) and binding of T3 to cytosolic proteins (i.e., cytosolic TH receptors, TR). These can signal through transduction pathways involving MAPKs, PKC, AKT, and PI3‐K‐AKT/PKB. TH‐dependent activation of integrins gives rise to similar signaling pathways that, in turn, may result in gene transcription. TR‐dependent genomic action requires TREs for the recognition of genes for direct transcriptional regulation [early expression (early)]. Some of these target genes serve as intermediate factors (e.g., NRF‐1, NRF‐2, PPARγ, and transcriptional coactivators such as PGC‐1α and PGC‐1β) and regulate a second series of TH target genes [late expression (late)]. The transcription of these genes can be either dependent or not by a TRE recognition by TR. Also nongenomic actions of TH (e.g., activation of kinases such as p38 MAPK and AMPK) can lead to modulation of transcription factors (not depicted mechanisms). Intermediate factors can enter the mitochondrion finally modulating mitochondrial functions such as biogenesis, oxygen consumption, and gene expression. In the TH‐dependent nucleus‐mitochondrion cross‐talk an important role is also played by the nuclear‐encoded transcription factor mtTFA, a key modulator of mitochondrial DNA (mtDNA) stabilization. In addition, mitochondria contain two N‐terminally truncated forms of the TR alpha 1 receptor isoform, with molecular weights of 43 (p43) and 28 kDa (p28). Whereas the function of p28 remains uncertain, p43 can be considered a T3‐dependent transcription factor of the mitochondrial genome.

Figure 2. Schematic representation of the mitochondrial respiratory chain and the main mitochondrial “sites” of action of TH. The main mitochondrial respiratory complexes are represented: I (Complex I, NADH dehydrogenase), II (Complex II, Succinate dehydrogenase), III (Complex III, ubiquinone cytochrome c‐reduttase), IV (complex IV, cytochrome c‐oxidase), V (Complex V, ATP synthetase), C (cytochrome c), and Q (coenzyme Q). Transfers electrons from reduced coenzymes to O₂ and, pumping out H⁺ from the matrix to the intermembrane space, generates an electrochemical gradient, ΔμH⁺, which provides the driving force for ATP synthesis by Complex V. H⁺ can also enter the matrix by mechanisms not coupled to ATP synthesis either directly, across the lipid bilayer, or indirectly, by protein‐mediated transport [e.g., ADP/ATP carrier (ANT) and UCP]. Some sites of ROS production into the intermembrane space and the matrix are depicted too. As discussed in the main text, TH not only affects mitochondrial biogenesis but also significantly influences mitochondrial oxygen consumption. T3, in particular, elicits both short‐term and delayed stimulation of mitochondrial oxidative capacity. The early influence has been suggested to occur through protein synthesis independent extranuclear mechanisms (e.g., a direct T3 influence through mitochondrial specific T3‐binding sites). The more delayed influence of T3 upon mitochondrial respiration probably results from nuclear/transcriptional mechanisms that in turn modulate phospholipid turnover and uncoupling protein expression, finally leading to an increased inner membrane proton leak. The biochemical/molecular events underlying such modulation of mitochondrial energy efficiency are tissue specific (for details, see text).