Tour-de-Force

Tour-de-Force: Interplay between Mitochondria and Cell Cycle Progression Fall 2007IntroductionMitofusin 2 is a member of the mitochondrial outer membrane GTPases family of mammalian mitofusins.The structure of Mfn2, shown in Figure 4.1, is characterized by a GTPase domain, which is present on theN terminal of the protein. Both cytosolic parts of Mfn2 contain coiled coil domains. As for the midsection ofthe protein, a transmembrane domain affixes Mfn2 to the outer mitochondrial membrane (Ansgar, 2006).Figure 4.1:Schematic representation of Mfn2. In the outer mitochondrial membrane.Note that both the N- and C-terminals face the cytosol. HR1 and HR2indicate two heptad repeat regions, motifs that generally form coiled-coilstructures.To date, much research has elaborately explored the role of Mfn2 accounting for the morphologicalchanges of mitochondria. The protein enables mitochondria to tether, which eventually mediates fusion(Yan Zhanga, 2007). Furthermore, the role of dysfunctional Mfn2 has been investigated extensively. Amutated form of the protein compromises many of the vital functions of the mitochondria, leading tovarious neurodegenerative disorders such as that of Charcot-Marie-Tooth 2 (Ansgar, 2006).However, perhaps the focus on the role of Mfn2 in mitochondrial morphogenesis has overshadowedmultiple other functions this protein exhibits. Mfn2 plays an important role in maintaining membranepotential and thus OXPHOS activity. It is known that overexpression of Mfn2 can upregulate OXPHOScomplexes resulting in a higher membrane potential (Pich et al., 2005). Nonetheless, as Mfn2 has beenshown to be involved in apoptosis (Shen et al., 2007) and cell cycle arrest pathways (Chen et al., 2004) itcan be safely assumed that the functions of Mfn2 are not merely restricted to the mitochondria but alsoare also effective in the cytosol.Thereby, this research will focus on exploring the various functions of Mfn2, apart from those exhibited inthe morphology of the mitochondria (Figure 4.2). Rather will this research focus on Mfn2 as a regulatingfactor between the functionality of the mitochondria and the progression of the cell cycle.Since Mfn2 is capable of upregulating OXPHOS, it could be targeted when energy demands change. It isthought that during the cell cycle OXPHOS activity should be regulated, as different demands of energycorrespond to the different phases of the cell cycle (Cuezva et al., 2006). Therefore, it is hypothesized thatMfn2 expression and/or activity fluctuates throughout the cell cycle. By regulation of Mfn2 levels during theSCI 332 Advanced Molecular Cell Biology Research Proposal 74