Control of Mitochondrial Function and Cell Cycle Progression by PGC-1-Related Coactivator (PRC)Public Deposited
PRC is a PGC-1 coactivator family member responsive to serum growth factors and up regulated in proliferating cells. Unlike PGC-1α and PGC-1β, PRC has not been studied extensively and and its function or regulation remains largely unknown. Both PGC-1α and PGC-1β have been shown to be important regulators of mitochondrial biogenesis, in part through the nuclear respiratory factor-1, NRF-1. PRC has been found to directly interact with and co-activate NRF-1, but no direct link between PRC and mitochondrial proliferation has been reported. We hypothesize that PRC controls mitochondrial function linked to cell proliferation. In this dissertation project, we established that PRC can trans-activate the promoters of genes encoding mitochondrial transcription factors through NRF-1 and NRF-2, and we found a positive correlation between PRC up regulation by serum and increased expression of these factors. Furthermore, we demonstrated that PRC likely functions through NRF-2 in vivo by existing in a complex with another coactivator involved in cell proliferation and NRF-2. Another correlation between PRC and mitochondrial proliferation and cell growth was demonstrated by the inhibition of respiratory growth on galactose by a dominant negative fragment of PRC. Also, the induction of PRC by serum is mainly transcriptional and does not require de novo protein synthesis, and serum stimulation markedly increases occupancy of the cytochrome c promoter in vivo by PRC. The most important focus of this dissertation was to investigate whether PRC can stimulate mitochondrial biogenesis directly by gain- and loss-of-function studies. The stable silencing of PRC expression with two different short hairpin RNAs resulted in cell cycle defects and a severe reduction in respiratory function in the context of proliferation of structurally abnormal mitochondria, establishing that PRC is an important regulator of cell proliferation, respiratory gene expression and mitochondrial biogenesis. Global gene profiling of PRC deficient cells also indicated more pleiotropic effects of PRC. Unfortunately, PRC gain-of-function studies remained inconclusive. Together, these studies help us gain more insight in the regulation of the nucleo-mitochondrial communication and may lead to a better understanding and possibly therapeutic interventions for human mitochondrial diseases.