**3. Nuclear / mitochondrial targets of TH**

TH effects in the mitochondrial context may consist of long-term effects that are dependent upon gene expression, and short-term effects that are refractory to inhibitors of protein synthesis. An important finding reported by Tata et al (2), indicated that the calorigenic activity of TH was abrogated by actinomycin D, implying that TH-induced mitochondrial uncoupling is mediated by modulating nuclear gene expression of respective mitochondrial and/or extra-mitochondrial proteins. These results were followed by extensive studies ((22, 23) and others) that resulted in discovering the nuclear TH receptors (THR) of the superfamily of nuclear receptors, acting as target for TH in modulating nuclear gene expression. THR are encoded by two distinct tissue-dependent genes coding for splice variants of the THRbrain, bone, heart) and THRliver, brain, heart) isoforms. THR homodimers or heterodimers with other members of the superfamily of nuclear receptors (e.g., retinoic X receptor (RXR)) may interact with TH-response elements (TRE) in the promoters of TH-responsive genes, resulting in transcriptional activation or suppression as function of transcriptional co-activators or co-suppressors recruited by TH/THR to the transcriptional complex of respective promoters. Indeed, TH binding to nuclear THR results in direct transcriptional activation of the expression of genes coding for components of mitochondrial oxidative phosphorylation (i.e. βF1-adenosine triphosphatase, adenine nucleotide translocase (ANT), cytochrome c1) (24, 25), or genes coding for intermediate factors that are indirectly involved in promoting the nuclear expression of mitochondrial components (i.e. nuclear respiratory factors 1 and -2, peroxisome proliferator-activated receptor-γ coactivator-1) (26), or in stimulating mitochondrial DNA replication (27). Hence, TH-induced mitochondrial uncoupling was believed to be accounted for by TH-induced gene expression of respective protein targets that modulate mitochondrial oxidative phosphorylation. In pursuing putative proteins involved in TH-induced mitochondrial uncoupling, a number of candidates have been suggested. These included the adenine nucleotide translocase, proteins that are involved in phosphatidylglycerol and cardiolipin synthesis (28), and in particular the mitochondrial uncoupling proteins (UCPs).
