Tour-de-Force

Tour-de-Force: Interplay between Mitochondria and Cell Cycle Progression Fall 2007General ConclusionThis research proposal focuses on the various regulative influences the mitochondria have on thecell cycle and cell cycle progression, and vice versa. The goal of this research program, consisting of fourprojects, is to establish a more complete picture of the mechanisms through which the cell cycle and themitochondria correspond with one another. The links between the cell cycle and the mitochondria areimportant to be established as the mechanisms regulate to some extend the two very important cellularprocesses of cell cycle progression and mitochondrial activity. Next to the gaining of knowledge that willbe achieved throughout the conductance of the proposed research, better understanding of severaldiseases, such as cancer and Charcot Marie tooth may be developed.In the first project, the existence of a metabolic cycle was discussed. ROS fluctuation throughout the cellcycle is proposed to be studied. In addition, the relative contribution of mitochondria to ROS productionshould be investigated in comparison to other known ROS producers. Lastly, the influence of ROS on theG2/M phase transition should be explored in order to establish a clear link on how ROS levels regulate cellcycle progression. Through performing this research, a strong interaction between the cell cycle andmitochondria through ROS might be indicated.In the second part of this proposal, focus was placed on the energy checkpoint in G1 phase. Thepathways through which high levels of activated AMPK can induce cell cycle arrest should be explored. Alink between energy-producing mechanism and cell cycle arrest is aimed to be better understood, and adirect link between AMPK and energy-producing mechanisms is proposed. Lastly, it will be investigatedwhether, and how, mitochondrial morphology changes after the cell goes into cell cycle arrest. Throughthe accomplishment of this research proposal, the role and functionality of AMPK in the regulativeinteraction between energy status in the cell and cell cycle arrest will be better determined.Consecutively, a research that is mainly focused on the role of the cell cycle for mitochondrialbiogenesis was proposed. This research is necessary to improve the perception of the dependence ofmitochondrial biogenesis on cell cycle progression. The role of nuclear respiration factor (NRF) is ofparticular interest as it is a factor which is capable of activating the transcription of various mitochondrialcomponents. The main aim of this research is to investigate the dynamics of mitochondrial biogenesisduring the cell cycle and to understand how induction of mitochondrial biogenesis by different factors maybe coordinated.Lastly, the regulative interaction between mitochondria and cell cycle progression is aimed to beexplained through the activities of mitofusin2. The fluctuations of Mfn2 levels throughout the cell cycle areinvestigated and a possible mechanism of oxidative phosphorylation maintenance with the aid Mfn2 ishypothesized. A mechanism of Mfn2 cleavage is proposed. Through the latter, the generation of both themitochondrial and the cytosolic isoforms with their opposing roles may be explained. Furthermore, itinvestigates the ability of cytosolic Mfn2 to inhibit Ras. Lastly, the influence of cyclins on Mfn2 levels andactivity are assessed to round up the circle of regulative interaction between the cell cycle andmitochondria through Mfn2.To conclude, the four projects share in common much more than merely the general theme ofresearch. Both project one and two shed a focus on metabolic activities, which is also a common aspectwith project four. Even though throughout the different projects several pathways to cell cycle arrest areexplored independently, in practice of reality they might all be linked to a general pathway of cell cyclearrest. Project three focuses on the nuclear encoding of mitochondrial proteins. Mfn2, discussed in projectfour might be influenced by NRF. Since the four topics are linked by various means, a complete picturewill not be provided throughout one individual project. Rather, throughout the performance of all fourproposals, a more lucid picture will be created, and a broader platform of background information forfuture research, will be provided.SCI 332 Advanced Molecular Cell Biology Research Proposal 94