Tour-de-Force

Tour-de-Force: Interplay between Mitochondria and Cell Cycle Progression Fall 2007Hypothesis 5: Cyclin D1 or cyclin E can mediate Mfn2 production or activityCyclins in combination with their cdk’s play an important role in cell cycle progression and in the regulationof mitochondrial activity. It has been demonstrated, for example, that cyclin B regulates mitochondrialfusion. The protein binds to Drp1 on Ser 585 (Taguchi, 2007), where it directly induces fission. Mfn2 alsohas a Ser 442 PKA phosphorylation site (Kuang-Hueih Chen1 2004). This site might have the samefunction as the SER 585 in Drp1, i.e. a target for cyclin mediated activation.In 2000, Alt et al. proved that cyclin D1 is capable of influencing mitochondrial activity. Decreasedcyclin D1 levels correspond to increased mitochondrial activity, whereas normal cyclin D1 levels repressmitochondrial activity (Sakamaki, 2006). Studies show that cyclin E can take over the functions of cyclinD1. In addition, analysis suggests that cyclin E is the major downstream target of cyclin D (Geng, 1999).Cyclin E is demonstrated to be an important downstream target of AMPK, when insufficient levels of ATPare available in the cell, which will lead to increased levels of AMP, AMP can activate the energy sensorAMPK. In turn, AMPK can activate many upstream targets, including p53. P53 is a cell cycle regulator thathas the capability of inducing cell cycle arrest via reduction of cyclin E levels. Therefore, it is hypothesizedthat after cyclin E is downregulated by p53, this will lead to increased ATP production and mitochondrialactivity. One of the downstream targets in this proposed pathway might very well be Mfn2 since Mfn2overexpression results in an upregulation of OXPHOS (Pich et al., 2005) (Figure 4.3).ATPCyclin E can restore Cyclin D1 deficiency Weexpect Cyclin E to be responsible for mtMfn2downregulatIonAMPKp53p21InhibitsCyclin EATPOXPHOMfn2When cyclin E is able* toinhibit Mfn2 production ↓Cyclin E ↑Mfn2* Supported by the fact thatcyclin D1 deficiency causesincrease in oxidative glycolsis[Sakamaki,.T. 2006] leading todisease.Figure 4.3: Scheme of proposed pathway LEGENDIn addition, as hypothesized by group 1, one could imagine that a reduction of OXPHOS would bedesirable from pre-S-phase through S-phase. We know such a “metabolic cycle” exists in yeast (Tu et al.,2005) but is not yet discovered in mammalian cells. Since Mfn2 loss of function decreases oxidation, wepropose a role for Mfn2 in this downregulation of OXPHOS. Both cyclin D1 and cyclin E are candidates forthe direct or indirect inhibition of Mfn2, because both cyclins are major players in the G1/S phasetransition (Resnitzky et al., 1994). In addition to that, they are the only cyclins present at high levels duringpre-S-phase. We hypothesize that, starting in pre-S-phase and mediated by cyclin D1 or E, either Mfn2levels decrease, or the activity by Mfn2 goes down.SCI 332 Advanced Molecular Cell Biology Research Proposal 85