Tour-de-Force

Tour-de-Force: Interplay between Mitochondria and Cell Cycle Progression Fall 2007that ROS are necessary for G 1 /S transition (Havens et al., 2006). To identify the influence of a redox cycleon the entire cell cycle, this research will focus on the G 2 /M transition.Background InformationThis section will present relevant background information. Three main topics will be discussed. First,information on the metabolic cycle will be presented, which will be followed by a discussion of ROS andthe redox cycle. Lastly, the effects of ROS on the cell cycle will be elaborated on.Existence of a metabolic cycleIt has been shown that there is a cyclic change in metabolic activity in yeast that is coordinated with thecell cycle (Tu et al., 2005; Reinke and Gatfield 2006). A period where metabolism is mainly respiratory isalternated with a period where anaerobic metabolism is prevalent. The entire cycle can be divided intothree parts: an oxidative phase, a reductive/building phase and a reductive/charging phase. In the first,oxidative, phase, respiration, oxidative phosphorylation and ATP production are high, meaning that themitochondria are metabolically active. In the reductive/building phase DNA is replicated and the celldivides, while respiration is greatly reduced. Lastly, in the reductive/charging phase, the cell prepares forthe next respiratory burst through non-respiratory modes of energy and protein degradation (Reinke andGatfield, 2006). This cycle is accompanied by a highly organized transcriptional cycle of genes thatencode for proteins associated with energy production, metabolism and protein synthesis (Tu et al., 2006).The transcription of these nuclear genes involved in mitochondrial metabolism starts right at the end of theoxidative phase (Reinke and Gatfield 2006). This indicates that after the oxidative phase in whichmitochondria are very active, the mitochondria switch to a resting state to rebuild their resources. Theexistence of a metabolic cycle and the accompanied transcriptional cycle in yeast indicates thatmetabolism and cell cycle progression can be closely linked through gene expressionIn mammalian cells, such a metabolic cycle has never been found. However, there are indications thatmitochondria can alternate between metabolic states depending on availability of ADP, substrates foroxidative phosphorylation and oxygen. Such a change in mitochondrial activity can occur in nonproliferatingcells, but there might also be transcriptional regulation of metabolic activity, potentially relatedto the cell cycle. It has been shown that when cyclin D1 is knocked-out there is an increase inmitochondrial activity. This is accompanied by increased activity of NRF-1, a transcription factor controllingmany mitochondrial proteins (Wang et al., 2006; Sakamaki et al., 2006). As cyclin D1 is involved in theG1/S transition, this is another indication that mitochondrial metabolic activity and the cell cycle caninteract.An accurate measure of mitochondrial metabolic activity is oxygen consumption. Mitochondria account forapproximately 90% of the cellular oxygen consumption, meaning that oxygen consumption can be directlyrelated to mitochondrial activity (Boveris et al., 2006; Gnaiger, 2007). In a study in yeast, oxygenmeasurements were used to measure mitochondrial activity throughout the cell cycle (Tu et al., 2006),which led to the identification of the yeast metabolic cycle.Another measure of mitochondrial metabolic activity is the mitochondrial membrane potential. Thispotential is formed by protons that are pumped into the mitochondrial intermembrane space by theelectron transport chain. Subsequently, when protons flow back through its pore, the ATPase uses thisgradient to generate ATP. It has been reported that mitochondrial membrane potential decreases whenthe mitochondria are in a resting state, while it increases in active mitochondria (Boveris et al. 2006).Existence of a redox cycleIn mammalian cells, fluctuations in the intracellular redox state have been proposed to work as a growthregulator during the cell cycle. The cell contains many electron donors and electron receptors, orreductants and oxidants, respectively. Two examples are the NAD(P)H/NAD(P)+ balance, and reactiveoxygen species and their antioxidants. The most accurate description of a redox cycle would be afluctuation in cellular reduction potential, as this takes into account all cellular reductants and oxidants.SCI 332 Advanced Molecular Cell Biology Research Proposal 11