Tour-de-Force

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Tour-de-Force: Interplay between Mitochondria and Cell Cycle Progression Fall 2007The generation of metabolic activity, mainly enabled by the mitochondria, is a major activity of allcells. Most energy in the cell is obtained from oxydative phosphorylation within the mitochondria. Duringoxidative phosphorylation, electrons stemming from NADH and FADH2 combine with oxygen. Theelectron transport chain uses the energy released from oxidation/reduction reactions to firstly produce aproton gradient across the inner mitochondrial membrane. In the process of chemiosmosis, protons flowback across the membrane in order to produce ATP from ADP (Figure 2).Figure 2 Oxidative Phosphorylationcreates energy through the electrontransport chain and chemiosmosisSource: Oxidation-Reduction Reactions andProton Pumping in Oxidative Phosphorylation;http://www.chemistry.wustl.edu/~courses/genchem/Tutorials/Cytochrome/ProtonPump.htmAs the mitochondria are the main suppliers of energy within the cell, and all cellular processesrequire energy, it naturally follows that mitochondrial activity has great influence on the cell as a whole.Furthermore, as a byproduct of oxidative phosphorylation, radical oxygen species are produced that havegreat impact within the cell as well. Through the production of these molecules, mitochondria are believedto also have a regulative influence on cell cycle progression.Mitochondria have been shown to be very dynamic organelles. They are known to fuse and divideagain, and it remains relatively unclear what the function of these processes is. The most popularhypothesis at this moment is that the fusion and fission of mitochondria ensures that the mitochondrialgenetic information is distributed evenly over all mitochondria, which might be necessary after mutations.Additionally, various mitochondrial proteins are transcribed in the nucleus. Furthermore, cell cycleproteins have been proven to affect the mitochondria directly in several ways. Therefore it is believed thatthe cell cycle and cell cycle progression highly influence mitochondrial activity, morphology and biogenesis.Cell cycle and mitochondrial activity: making the linkAccording to the widely accepted principle of endosymbiosis, mitochondria started off as onesingle bacterium that was taken up by another, larger, cell. This makes mitochondria remarkableorganelles having their own genetic information and being able to divide independently from their host cell.However, over the course of time, the bacterium and the larger cell have been becoming increasinglydependent of each other. Nowadays, in animal cells, mitochondria still have their own genetic system,although not all mitochondrial proteins are encoded by this internal genome. Mitochondria therefore arehighly influenced by the general transcription of proteins in the nucleus, and communication is known totake place between the nucleus and mitochondria. Because of their extraordinary origin, thiscommunication between the nucleus and mitochondria is a very important example of the creativity ofevolution. It clearly demonstrates how systems evolved to form a better functioning system. It has beenproposed that the two regulate each other’s activity in various ways. This research proposal aims to give amore complete overview of the communication between two of the most important cellular aspects: thecell cycle, allowing the cell grow and to divide, and the mitochondria, once an organism itself.This research proposal focuses on the various regulative influences that the mitochondria have onthe cell cycle and cell cycle progression. Additionally, several propositions are made on the regulative roleSCI 332 Advanced Molecular Cell Biology Research Proposal 6
Tour-de-Force: Interplay between Mitochondria and Cell Cycle Progression Fall 2007of cell cycle progression on the mitochondria. Through testing the hypotheses in this research proposal,the understanding of the regulative interaction between mitochondria and the cell cycle will be greatlyenhanced.Firstly, the existence of a metabolic cycle will be discussed. In yeast, a metabolic cycle hasalready been proven to exist, but there are also indications for its existence in mammalian cells. It ishypothesized that a change in mitochondrial activity has an effect on the cell cycle through ROSproduction. There is evidence that certain levels of ROS are necessary for cell proliferation, and someregulators of the cell cycle have been found to act in a redox-dependent manner. Firstly, ROS fluctuationthroughout the cell cycle will be studied. In addition, the relative contribution of mitochondria to ROSproduction will be investigated in comparison with other known ROS producers. Lastly, the influence ofROS on the G2/M phase transition will be investigated in order to establish a clear link on how ROS levelsregulate cell cycle progression. Through performing this research, a strong interaction between the cellcycle and mitochondria through ROS might be indicated.In the second part of this proposal, focus will be placed on the energy checkpoint in G1 phase. Inthis energy checkpoint, AMPK is the protein that will be focused on most. AMPK is an enzyme thatevaluates the ratio of ATP and AMP within the cell, after which cell cycle arrest can be achieved in case ofinsufficient energy levels. The pathways through which high levels of activated AMPK can induce cellcycle arrest will be explored. A link between energy-producing mechanism and cell cycle arrest is aimed tobe better understood, and a direct link between AMPK and energy-producing mechanisms is proposedand studied. Lastly, it will be investigated whether, and how, mitochondrial morphology changes after thecell goes into cell cycle arrest. Through accomplishment of this research proposal, it will be betterunderstood how AMPK functions in the regulative interaction between energy status in the cell and cellcycle arrest.To continue, a research that is mainly focused on the role of the cell cycle for mitochondrialbiogenesis is proposed. Whereas the preceding two proposals are mainly aimed at explaining the effectsand consequences of mitochondrial products on the cell cycle, this research is necessary to improveunderstanding about the dependence of mitochondrial biogenesis on cell cycle progression. The role ofNRF (nuclear respiration factor) is of particular interest as this factor is capable of activating thetranscription of various mitochondrial components. The main aim of this research is to investigate thedynamics of mitochondrial biogenesis during the cell cycle and to understand how induction ofmitochondrial biogenesis by different factors may be coordinated.Lastly, the regulative interaction between mitochondria and cell cycle progression is aimed to beexplained through the activities of another remarkable protein, namely mitofusin2. Mitofusin2 is known forits role in the regulation of mitochondrial fusion and fission, but it has been proposed to have many otherintriguing functions. Mfn2 is interesting as it is a potential target for cell cycle regulation by energyproduction. Therefore, it is explored how Mfn2 levels vary throughout the cell cycle and a possiblemechanism of oxidative phosphorylation maintenance by Mfn2 is proposed. Remarkably, Mfn2 can alsoexist in the cytosol where it has a seemingly contradicting function, namely the potential to induce cellcycle arrest through inhibition of Ras. A possible mechanism of cleavage is proposed throughout whichthe occurrence of both isoforms and their opposing roles might be explained. Furthermore, it will beinvestigated into more detail how cytosolic Mfn2 functions to inhibit Ras. Lastly, the influence of cyclins onMfn2 levels and activity is assessed to round up the circle of regulative interaction between the cell cycleand mitochondria through Mfn2.These four projects, all focusing on the link between the cell cycle and mitochondria, mayit be on very different aspects, are shown in figure 3.SCI 332 Advanced Molecular Cell Biology Research Proposal 7
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