Tour-de-Force

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Tour-de-Force: Interplay between Mitochondria and Cell Cycle Progression Fall 2007DiscussionThis research is aimed at establishing the regulatory role of the PPAR-family in mitochondrial biogenesisduring cell cycle progression and in the metabolic burst. Therefore, the main hypothesis this researchfocuses on is: PRC and PGC-1 are involved in the cell cycle as important regulators of mitochondrialbiogenesis, in cells transitioning from quiescent to proliferating, directly via the metabolic burst.During the first year of the research a solid basis for the rest of the research is set. Previously conductedstudies and experiments are repeated in the cell lines used in this project, to suit the experimental context.The ratio of mitochondrial DNA and nuclear DNA is examined in continuously proliferating cells and ininducible cells, i.e. the metabolic burst. Also, the mitochondrial mass throughout the cell cycle isestablished, as this gives an indication as to mitochondrial biogenesis throughout the cell cycle.Knowledge of these aspects is important in the rest of the research.In the second year the focus shifts to the upstream regulation of the PPAR family. Important aspectsconcerning two upstream regulatory pathways of the PPAR family are determined: the MAPK-Erk pathwayand MAPK-p38 pathway. By checking presence of these compounds and performing kinase assays theregulation of these pathways on the PPAR family is determined. Knowledge of this upstream regulationmight prove invaluable to further research in mitochondrial biogenesis. With the activation patterns of thePPAR family determined, it could become possible to closer regulate mitochondrial biogenesis.In the final part of this research, focus is shifted downstream of the PPAR family to their main target, NRF-1, and a regulation of cell cycle involved complexes on mitochondrial biogenesis is established. As anaddition, the extent of similar functionality of NRF-2 is compared to NRF-1. The regulation of thesecompounds through phosphorylation, both activation and inhibition, is examined. The inhibitory influenceof different cyclin/cdk complexes present mainly in the G1 phase of the cell cycle, is established, andcompared to activation effects of PRC. Knowledge of downstream activities of PRC provides insight to itsdirect positive effects on mitochondrial biogenesis. More so, the inhibitory influence of important cell cyclecomplexes shows how the cell cycle regulates mitochondrial biogenesis, and therefore provides its ownenergy. A functional comparison between PRC and cyclin/cdk complexes reveals how mitochondrialbiogenesis is coordinated with the cell cycle.This research provides a very useful basis for future research into mitochondrial behavior throughout thecell cycle. The PPAR family has been established to be the main regulatory family of mitochondrialbiogenesis and a better understanding of the up- and downstream regulation of this family providesinvaluable insight into cellular-mitochondrial communications. Unfortunately, there are many moreregulatory proteins and pathways involved in mitochondrial biogenesis that remain to be determined. Thisresearch tries to stimulate more investment in this research area, as it could prove invaluable to have acomplete understanding of mitochondrial biogenesis in the cell cycle.SCI 332 Advanced Molecular Cell Biology Research Proposal 70
Tour-de-Force: Interplay between Mitochondria and Cell Cycle Progression Fall 2007ReferencesAkimoto, T. et. al. (2005) “Exercise Stimulates PGC-1a Transcription in Skeletal Muscle through Activation of the p38 MAPKPathway” The Journal of Biological Chemistry 280, 19587-19593Andersson, Ulf, et al., (1999), Mechanisms controlling mitochondrial biogenesis and respiration through thremogenic coactivatorPGC-1, Cell, Vol. 98, pp115-124Andersson, U. and Scarpulla R. C., 2001, PGC-l-related coactivator, a novel, serum-inducible coactivator of nuclear respiratoryfactor 1-dependent transcription in mammalian cells, Molecular Cell Biology, 21, 3738-3749.Ashley, Harris and Poulton (2005) “Detection of mitochondrial DNA depletion in living human cells using PicoGreen staining”.Experimental Cell Research 303, 432–446Bergeron, R. et. al. (2001) “Chronic activation of AMP kinase results in NRF-1 activation and mitochondrial biogenesis” Am J PhysiolEndrinol Metab 281, El340-El346Carthon, Bradley C. et al. (2005) “Genetic Replacement of Cyclin D1 Function in Mouse Development by Cyclin D2” Molecular andCellular Biology 25, 1081-1088Chau C.A., Evans M.J., and Scarpulla R.C., 1992, “Nuclear Respiratory Factor 1 Activation Sites in Genes Encoding the Gama-Subunit of ATP Synthase, Eukaryotic Initiation Facto 2-alpha, and Tyrosine Aminotrahsferase”, Journ. Biol. Chem., 267(10), 6999-7006.Coll, T., et. al, (2006) “Palmitate-Mediated Downregulation of Peroxisome Proliferator-Activated Receptor-γ Coactivator 1α inSkeletal Muscle Cells Involves MEK1/2 and Nuclear Factor-κB Activation” Diabetes 55, 2779-2787Delghandi, M. P. et al., (2005) “The cAMP signalling pathway activates CREB through PKA, p38 and MSK1 in NIH 3T3 cells” CellularSignaling 17 (11), 1343-1351Duguez, S. et. al. (2001) “Mitochondrial Biogenesis during skeletal muscle regeneration” AJP – Endocrinology and Metabolism 282,E802-E809Fan, M. et. al. (2004) “Suppression of mitochondrial respiration through recruitment of p160 myb binding protein to PGC-1α:modulation by p38 MAPK” Genes & Development 18, 278-289Gleyzer, N., Scarpulla, R.C., and Vercauteren, K., (2005), Control of Mitochondrial Transcription Specificity Factors (TFB1M andTFB2M) by Nuclear Respiratory Factors (NRF-1 and NRF-2) and PGC-1 Family Coactivators, Molecular and Cellular Biology 25(4),1354-1366Gugneja, S., and Scarpulla R. C., 1997, Serine phosphorylation within a concise amino-terminal domain in nuclear respiratory factor1 enhances DNA binding, Journal of Biological Chemistry, 272, 18732-18739Herzig R.P., Scacco S., and Scarpulla, R.C. 2000, Sequential serum-dependent activation of CREB and NRF-1 leads to enhancedmitochondrial respiration through the induction of cytochrome c, Journal of Biological Chemistry, 275, 13134-13141.Kuningas, M. et. al. (2007) “SIRT1 Gene, Age-Related Diseases, and Mortality: The Leiden 85-Plus Study” The Journals ofGerontology Series A: Biological Sciences and Medical Sciences 62, 960-965Lee, S. et al. (2007) “Cell cycle-dependent mitochondrial biogenesis and dynamics in mammalian cells” Science Direct 357, 111-117Lin, J. et. al. (2001) “PGC1b: A Novel PGC1 Related Transcription Coactivator Associated with Host Cell Factor” J. Biol. Chem. 10,1074Lin, J. et al. (2005) “Metabolic control through the PGC-1 family of transcription coactivators” Cell Metabolism 1, 361-367Li, P. et. al., (2006) “Resident stem cells are not required for exercise-induced fiber-type switching and angiogenesis but arenecessary for activity-dependent muscle growth” American Journal of Physiology – Cell Physiology 290, C1467-C1468Mandal, S. et. al. (2005) “Mitochondrial Regulation of Cell Cycle Progression during Development as Revealed by the tenuredMutation in Drosophila” Developmental Cell 9, 843-854Martinez-Diez, M., Santamaria, G., Ortega, A.D., and Cuezva, J.M., (2006), Biogenesis and Dynamics of Mitochondrial during theCell Cycle: Significance of 3’UTRs, PLoS ONE 1(1), e107Melloul, D. and Stoffel, M. (2004) “Regulation of Transcriptional Coactivator PGC-1α” Sci. Aging Knowl. Environ. 2004, pe9Ongwijitwat, S. & Wong-Riley, M.T. (2005) “Is nuclear respiratory factor 2 a master transcriptional coordinator for all ten nuclearencodedcytochrome c oxidase subunits in neurons?” Gene 360, 65-77Petersen, C. et. al. (2005) “The p38 MAPK pathway mediates interleukin-1-induced Sertoli cell proliferation” Cytokine 32, 51-59Petit, Maftah, Ratinaud and Julien (1992), “10N-Nonyl acridine orange interacts with cardiolipin and allows the quantification of thisphospholipid in isolated mitochondria” European Journal of Biochemistry 209, 267-273Presley, Fuller and Arriaga (2003) “MitoTracker Green labeling of mitochondrial proteins and their subsequent analysis by capillaryelectrophoresis with laser-induced fluorescence detection” Journal of Chromotography B issue 1, 141-150SCI 332 Advanced Molecular Cell Biology Research Proposal 71
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