Tour-de-Force

Tour-de-Force: Interplay between Mitochondria and Cell Cycle Progression Fall 2007DiscussionThis research is aimed at establishing the regulatory role of the PPAR-family in mitochondrial biogenesisduring cell cycle progression and in the metabolic burst. Therefore, the main hypothesis this researchfocuses on is: PRC and PGC-1 are involved in the cell cycle as important regulators of mitochondrialbiogenesis, in cells transitioning from quiescent to proliferating, directly via the metabolic burst.During the first year of the research a solid basis for the rest of the research is set. Previously conductedstudies and experiments are repeated in the cell lines used in this project, to suit the experimental context.The ratio of mitochondrial DNA and nuclear DNA is examined in continuously proliferating cells and ininducible cells, i.e. the metabolic burst. Also, the mitochondrial mass throughout the cell cycle isestablished, as this gives an indication as to mitochondrial biogenesis throughout the cell cycle.Knowledge of these aspects is important in the rest of the research.In the second year the focus shifts to the upstream regulation of the PPAR family. Important aspectsconcerning two upstream regulatory pathways of the PPAR family are determined: the MAPK-Erk pathwayand MAPK-p38 pathway. By checking presence of these compounds and performing kinase assays theregulation of these pathways on the PPAR family is determined. Knowledge of this upstream regulationmight prove invaluable to further research in mitochondrial biogenesis. With the activation patterns of thePPAR family determined, it could become possible to closer regulate mitochondrial biogenesis.In the final part of this research, focus is shifted downstream of the PPAR family to their main target, NRF-1, and a regulation of cell cycle involved complexes on mitochondrial biogenesis is established. As anaddition, the extent of similar functionality of NRF-2 is compared to NRF-1. The regulation of thesecompounds through phosphorylation, both activation and inhibition, is examined. The inhibitory influenceof different cyclin/cdk complexes present mainly in the G1 phase of the cell cycle, is established, andcompared to activation effects of PRC. Knowledge of downstream activities of PRC provides insight to itsdirect positive effects on mitochondrial biogenesis. More so, the inhibitory influence of important cell cyclecomplexes shows how the cell cycle regulates mitochondrial biogenesis, and therefore provides its ownenergy. A functional comparison between PRC and cyclin/cdk complexes reveals how mitochondrialbiogenesis is coordinated with the cell cycle.This research provides a very useful basis for future research into mitochondrial behavior throughout thecell cycle. The PPAR family has been established to be the main regulatory family of mitochondrialbiogenesis and a better understanding of the up- and downstream regulation of this family providesinvaluable insight into cellular-mitochondrial communications. Unfortunately, there are many moreregulatory proteins and pathways involved in mitochondrial biogenesis that remain to be determined. Thisresearch tries to stimulate more investment in this research area, as it could prove invaluable to have acomplete understanding of mitochondrial biogenesis in the cell cycle.SCI 332 Advanced Molecular Cell Biology Research Proposal 70