Cross-talk between oxidative phosphorylation and nuclear transcription

The oxidative phosphorylation (OXPHOS) system is an essential process in essentially every eukaryotic cell. It is composed of five multimeric subunits encoded by the nuclear and the mitochondrial genomes. A concerted cross-talk between both genomes must take place or the assembly of a fully functional OXPHOS system. In this study, I have analyzed the effects of OXPHOS dysfunction on nuclear gene expression (mitochondrial-to-nucleus communication) as well as the factors involved in transcriptional regulation of nuclear OXPHOS genes (nuclear-to-mitochondrial communication).In the first chapter, I describe gene expression changes induced by mitochondrial dysfunction. Microarray experiments, real-time RT-PCR and reporter assays, among others confirm the effect of OXPHOS dysfunction in the regulation of several proteins involved in extracellular matrix remodeling. In this context, in vitro invasion assays confirmed that the effects of OXPHOS dysfunction on the nuclear genome result in an increased invasiveness of cultured cells.In the second chapter I studied transcriptional regulation of nuclear encoded OXPHOS subunits. By analyzing publicly available data, I was able to show that OXPHOS genes coexpress across different tissue in humans and mice. In addition, we show that subunits of each complex coexpress preferentially with each other over subunits of other complexes. These observations lead us to investigate if there are common transcription factors underlying OXPHOS coexpression. Performing a high-throughput computational analysis of all nuclear coded OXPHOS gene promoters, we were able to identify common factors enriched in these promoters. These findings correlated extremely well with published experimental data. Thus, this study constitutes the first comprehensive analysis of nuclear OXPHOS promoters in humans, mouse and rat.In conclusion, this thesis sheds light into the cross-talk between the nuclear genome and the OXPHOS system showing that there is a tight communication between the nucleus and the mitochondria.