Tour-de-Force

Tour-de-Force: Interplay between Mitochondria and Cell Cycle Progression Fall 2007Furthermore, AMPK, activated by glucose deprivation, phosphorylates IRS-1 at Ser-794. This leads to thesuppression of the PI 3-kinase/ Akt pathway and subsequent apoptosis. Via co-immunoprecipitation it wasshown that both α catalytic subunits of AMPK bind IRS-1 in response to glucose deprivation (Tzatsos andTsichlis, 2007).Therefore, we hypothesize that under low energy conditions, AMPK induces early G1 cell cyclearrest through the action of IRS-1 on the PI3-kinase pathway, which is illustrated in Figure 2.4.Figure 2.4: Proposed pathways for cell cycle arrest and apoptosis in G1.A novel role for p53 as a regulator of the cell cycle after AMPK activation has been indicated in recentresearch (Jones et al., 2005). It was found that p53 is required to induce AMPK dependent cell cyclearrest at the end of G1. Although p53 has been mainly acknowledged as a pro-apoptotic protein, recentfindings suggest that here p53 mediates AMPK induced, reversible cell cycle arrest. In this way p53promotes cell survival. However, these results implicate a role for p53 only in the checkpoint at the end ofG1, whereas its involvement in the early G1 checkpoint still needs to be elucidated.A well established checkpoint in G1 is the restriction point, R which solely depends on the availability ofgrowth factors. Up to this point a cell will enter quiescence if growth factors are not available. Once a cellpasses R its progression into S-phase is no longer dependent on growth factors (Cooper and Hausman,2007). In general, it is assumed that cells cannot go into cell cycle arrest beyond this point. However, toour knowledge the influence of energy deprivation on cell cycle progression after R, has not beeninvestigated so far.Mitochondrial network dynamicsIn the cell, mitochondria exist as a network of dynamic organelles. Mitochondria are generally connected,forming filaments that reach throughout the cytosol. Individual mitochondria undergo fusion and fission,and the balance between these dynamics determines the overall morphology of the network. The exactreason for this morphology is unknown (Rube and Bliek, 2004). Many theorize that it is a way to distributeenergy throughout the cell, because the mitochondrial membrane potential, critical for ATP production, isthe same throughout the filamentous structure (Westermann, 2002). The morphology of the network isknown to change when cells differentiate. In some cell types, such as myoblasts and spermatocytes theexpression levels of fusion proteins increase drastically during differentiation (McBride et al., 2006).Furthermore, in fully differentiated cells, the majority of mitochondria tends to be located in a specific partof the cell, depending on the cell type (Arakaki et al. 2006). In fibroblasts, the overall mitochondrialmorphology seems to be interconnected and extending throughout the entire cytosol (Westermann, 2002).Mitochondrial morphology and the cell cycleSCI 332 Advanced Molecular Cell Biology Research Proposal 41