Tour-de-Force

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Tour-de-Force: Interplay between Mitochondria and Cell Cycle Progression Fall 20071ROS2AMPKATP3NRF4Mfn2(C)Mfn2(M)Figure 3 The four projects outlined in this research proposal and their links between the cell cycle andmitochondriaMade by authorsEvidently, figure 3 is far from being complete, as other organelles, locations, proteins andprocesses will be discussed throughout the proposals. Additionally, the manners in which the projects linkin to each other by these additional mechanisms are not shown. Project 1 and 2 both look at cellularmetabolism, project 1 linking this strongly to the cell cycle while project 2 investigates the hypothesizedrelation between metabolism and AMPK. Additionally, both project 2 and 4 look into cell cycle arrest,project 4 via Mfn2 and the Ras pathway, and project 2 via AMPK and p53. The four projects, mitochondriaand the cell cycle and these individual links add up to a complete picture of the interplay between the cellcycle, mitochondrial dynamics, functioning and activity, apoptosis and cellular metabolism – they all addup to this program.Relevance of the topicThroughout this program, various aspects of the interplay between mitochondria and the cell cyclewill be addressed. Throughout performing all proposed research, the interplay will be better understood.The knowledge that will be gained is likely to be relevant to the development of medical therapy, asvarious diseases, such as cancer and Charcot Marie Tooth disease, originate from cell cycle defects ormalfunctioning mitochondria. However, the information by itself will greatly enrich our understanding of thecellular events that form the essence of life, since both the cell cycle and energy production are extremelyimportant processes in the cell. Their link, therefore, will greatly add to our general understanding of thecell.To conclude, it is proposed that the cell cycle is highly influenced by mitochondrial products suchas ROS and ATP, and mitochondria are bound to be influenced by cell cycle progression, so thatprocesses of interplay between the mitochondria and the cell cycle must exist. This program therefore isreferred to as the Tour-the-force. This research proposal could be seen as a tour past many different butimportant aspects of cellular functioning, for which we need two processes most: our cycle, the cell cycle,and our source of energy, provided by the mitochondria. It is hoped that the following research proposalwill provide an energetic tour through the regulative interaction pathways and mechanisms between thecell cycle and mitochondria.SCI 332 Advanced Molecular Cell Biology Research Proposal 8
Tour-de-Force: Interplay between Mitochondria and Cell Cycle Progression Fall 2007Regulation of Cell Cycle Progression ThroughMitochondrial ROS ProductionResearch Proposal byS.E. Bosch, H.T. Caylak, K.K. Dijkstra, N.C. Frenkel, D.D.J.J. van Hooijdonk, J.C. MostertAbstractThere are not many cellular functions that remain in a static mode while the cell is proliferating. Evenmitochondria, the metabolic engines of the cell, are suggested to change their activity during the cell cycle.In yeast, a metabolic cycle has already been proven to exist, but there are also indications for its existencein mammalian cells. The main product of mitochondria is ATP, but mitochondria also significantlycontribute to the production of reactive oxygen species (ROS). In this research proposal, it is hypothesizedthat a change in mitochondrial activity has an effect on the cell cycle through ROS production. There isevidence that certain levels of ROS are necessary for cell proliferation, and some regulators of the cellcycle have been found to act in a redox-dependent manner. However, many things are still unclear. Neverbefore has it been investigated how mitochondrial activity fluctuates throughout an entire mammalian cellcycle. Furthermore, evidence about ROS levels throughout the cell cycle is at times contradictory. In thisresearch, this gap will be filled by establishing fluctuations in mitochondrial activity and ROS levelsthroughout the cell cycle. In a second set of experiments, the relative contribution of mitochondria to ROSproduction will be studied in comparison with other known ROS producers. Lastly, the influence of ROS onthe G2/M phase transition will be investigated in order to establish a clear link on how ROS levels regulatecell cycle progression. As such, this research will be novel in investigating the links between mitochondrialmetabolic activity, ROS and cell cycle progression.SCI 332 Advanced Molecular Cell Biology Research Proposal 9
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