The nuclear co-activator PGC-1␣ is a pivotal regulator of numerous pathways controlling both metabolism and overall energy homeostasis. Inappropriate increases in PGC-1␣ activity have been linked to a number of pathological conditions including heart failure and diabetes mellitus. Previous studies (Puigserver, P., Adelmant, G., Wu, Z., Fan, M., Xu, J., O'Malley, B., and Spiegelman, B. M. (1999) Science 286, 1368 -1371) have demonstrated an inhibitory domain within PGC-1␣ that limits transcriptional activity. Using this inhibitory domain in a yeast two-hybrid screen, we demonstrate that PGC-1␣ directly associates with the orphan nuclear receptor estrogen-related receptor-␣ (ERR-␣). The binding of ERR-␣ to PGC-1␣ requires the C-terminal AF2 domain of ERR-␣. PGC-1␣ and ERR-␣ have a similar pattern of expression in human tissues, with both being present predominantly in organs with high metabolic needs such as skeletal muscle and kidney. Similarly, we show that in mice physiological stimuli such as fasting coordinately induces PGC-1␣ and ERR-␣ transcription. We also demonstrate that under normal conditions PGC-1␣ is located within discrete nuclear speckles, whereas the expression of ERR-␣ results in PGC-1␣ redistributing uniformly throughout the nucleoplasm. Finally, we show that the expression of ERR-␣ can dramatically and specifically repress PGC-1␣ transcriptional activity. These results suggest a novel mechanism of transcriptional control wherein ERR-␣ can function as a specific molecular repressor of PGC-1␣ activity. In addition, our results suggest that other co-activators might also have specific repressors, thereby identifying another layer of combinatorial complexity in transcriptional regulation.Co-activators represent an important class of molecules that can regulate transcription although they are unable to directly bind to DNA. In general, co-activators are thought to modulate gene expression through specific protein-protein interactions with classic transcription factors that possess DNA-binding domains. Similarly, another class of molecules called co-repressors can interact with transcription factors and subsequently inhibit downstream activation of gene expression. Although regulation of co-activator or co-repressor activity is incompletely understood, a number of recent reports have suggested that co-activators can be post-translationally modulated by targeted ubiquination as well as by various intracellular signaling pathways (1, 2). Given that a single co-activator can potentially interact with a number of different transcription factors, such regulation will undoubtedly be important in ultimately understanding the specificity of transcriptional regulation.The nuclear co-activator PGC-1␣ 1 was initially identified as a PPAR-␥ co-activator (3) but has since been recognize to function in cooperation with a number of other members of the nuclear receptor family including the glucocorticoid receptor, the thyroid hormone receptor, the mineralocorticoid receptor, and the estrogen receptor (4 -7). Bindin...
The reaction of ATP synthase (F0F1) is the final step in oxidative phosphorylation (OXPHOS). Although OXPHOS has been studied extensively in bacteria, no tissue-specific functions nor bioenergetic disease, such as mitochondrial encephalomyopathy and aging occur in these organisms. Recent developments of the Human Genome Project will become an important factor in the study of mammalian bioenergetics. To elucidate the physiological roles of human F0F1, genes encoding the subunits of F0F1 were sequenced, and their expression in human cells was analyzed. The following results were obtained: A. The roles of the residues in F0F1 are not only to transform the energy of the electrochemical potential (delta mu H+) across the membrane, but also to respond rapidly to the changes in the energy demand by regulating the intramolecular rotation of F0F1 with the delta mu H+ and the inhibitors of the ATPase. B. The roles of the control regions of the F0F1 genes, are to coordinate both mitochondrial DNA (mtDNA) and nuclear DNA (nDNA) depending on the energy demand of the cells, especially in muscle, C. The cause of the age-dependent decline of ATP synthesis has been attributed to the accumulation of mutations in mtDNA. However, the involvement of nDNA in the decline is also important because of telomere shortening in somatic cells, and age-dependent mtDNA expression analyzed with rho degree cells (cells without mtDNA).
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