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OMICS Group International is an amalgamation of Open Access publications and worldwide international science conferences and events. Established in the.

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Presentation on theme: "OMICS Group International is an amalgamation of Open Access publications and worldwide international science conferences and events. Established in the."— Presentation transcript:

1 OMICS Group International is an amalgamation of Open Access publications and worldwide international science conferences and events. Established in the year 2007 with the sole aim of making the information on Sciences and technology ‘Open Access’, OMICS Group publishes 500 online open access scholarly journals in all aspects of Science, Engineering, Management and Technology journals. OMICS Group has been instrumental in taking the knowledge on Science & technology to the doorsteps of ordinary men and women. Research Scholars, Students, Libraries, Educational Institutions, Research centers and the industry are main stakeholders that benefitted greatly from this knowledge dissemination. OMICS International also organizes 500 International conferences annually across the globe, where knowledge transfer takes place through debates, round table discussions, poster presentations, workshops, symposia and exhibitions.Open Access publicationsscholarly journalsInternational conferences About OMICS Group

2 About OMICS International Conferences About OMICS Group OMICS International is a pioneer and leading science event organizer, which publishes around 500 open access journals and conducts over 300 Medical, Clinical, Engineering, Life Sciences, Pharma scientific conferences all over the globe annually with the support of more than 1000 scientific associations and 30,000 editorial board members and 3.5 million followers to its credit. OMICS International has organized 500 conferences, workshops and national symposiums across the major cities including San Francisco, Las Vegas, San Antonio, Omaha, Orlando, Raleigh, Santa Clara, Chicago, Philadelphia, Baltimore, United Kingdom, Valencia, Dubai, Beijing, Hyderabad, Bengaluru and Mumbai.

3 4th International Conference and Exhibition on Metabolomics & Systems Biology April 29, 2015 – Philadelphia, USA Inmaculada Martinez-Reyes – Dr. Navdeep Chandel Lab – Northwestern University, Chicago Dissecting the distinct functions of mitochondria

4 Mitochondrial metabolism is necessary for tumorigenesis.

5 Acetyl-CoA FADH 2 FAD Citrate α-KG TCA Cycle NADH NAD + I II ATP-Citrate Lyase III V α-KG H2O2H2O2H2O2H2O2 NF  B HIF ? Ac Me HAT JMJD3 IV OAA Acetyl- CoA GlucosePyruvate H+H+ H+H+ H+H+ H+H+ O2O2 H2OH2O ADP ATP Q Q e-e- e-e- Q e-e- c e-e- c e-e- e-e- Mitochondria as signaling organelles. Catabolism AMPK AMP/ATP

6 What functions of mitochondrial metabolism are necessary for cell proliferation and epigenetics?

7 H+H+ ETC H2OH2O O2O2 H+H+ ADP ATP H+H+ Two functions of mitochondria: TCA cycle metabolites and membrane potential.  (ATP, ROS, Iron-sulfur clusters) TCA Metabolites (Acetyl-CoA, Succinyl-CoA) NADH/FADH2 NAD + /FAD

8 DNA polymerase gamma (POLG) is necessary for mitochondrial DNA (mtDNA) replication. Doxycycline (DOX) Dominant Negative (DN- POLG) Doxycycline Hans Spelbrink Doxycycline

9 Day 0 Day 3 Day 6 Day 9 WT PLOG + DOX DN PLOG + DOX Dominant negative POLG depletes mtDNA encoded RNA transcripts. Ty Wang Janine Santos

10 COXII SDHA Tubulin - - - - + + + + 0 3 6 9 DOX Days WT-POLG COXII SDHA Tubulin DOX Days DN-POLG - - - - + + + + 0 3 6 9 Dominant negative POLG depletes mtDNA encoded proteins.

11 Loss of mitochondrial DNA does not induce cell death.

12 Loss of mitochondrial DNA decreases oxygen consumption rate (OCR).

13 Loss of mitochondrial DNA decreases mitochondrial membrane potential.

14 Loss of mitochondrial DNA increases glucose catabolism. Biolog

15 Loss of mitochondrial DNA induces dependence on glycolysis for survival.

16 Loss of mitochondrial DNA induces AMPK activation. AMPK p-AMPK DN-POLG Tubulin DOX Days - - + + + + + + 0 0 3 3 6 6 9 9

17 Loss of mitochondrial DNA diminishes cell proliferation rate.

18 Quantification of Histone modifications using Silac. Yingming Zhao He Huang Minimal changes in methylation and acetylation of H2B and H4.

19 H3K27ac 036 9 DN-POLG H3K18ac DOX - + + + Days H3 total H3K9ac H3K14ac Loss of mitochondrial DNA decreases specific histone H3 acetylation.

20 Mitochondria metabolism is necessary for cell proliferation and specific histone acetylation.

21 H+H+ ETC H2OH2O O2O2 H+H+ ADP ATP H+H+ Two functions of mitochondria: TCA cycle metabolites and membrane potential.  (ATP, ROS, Iron-sulfur clusters) TCA Metabolites (Acetyl-CoA, Succinyl-CoA) NADH/FADH2 NAD + /FAD

22 Electron transport chain couples electron flux to proton pumping. C-I C-II C-III Q NADH NAD + FADH 2 FAD H+H+ H+H+ H+H+ O2O2 H2OH2O C-IV Cyt c

23 C-I C-II C-III Q NAD + FADH 2 FAD H+H+ H+H+ H+H+ O2O2 H2OH2O C-IV Cyt c NADH O2O2 H2OH2O AOX NDI1 NAD + NADH NDI1 mimics complex I and AOX bypasses complex III and complex IV. Eric Dufor

24 NDI1 and AOX expression uncouples electron flux from proton pumping in cells with depleted mitochondrial DNA. C-II Q NADH NAD + FADH 2 FAD O2O2 H2OH2O NDI1 AOX

25 NDI/ AOX H2OH2OO2O2 ATP 4- ADP 3- AOX-NDI1 expression restores electron flux but not membrane potential.  TCA Metabolites NADH/FADH2 NAD + /FAD

26 AOX-NDI expression does not restore mitochondrial DNA.

27 AOX-NDI expression restores oxygen consumption rate in isolated mitochondria. Seahorse Biosciences

28 Study of the metabolic profile of the cells DN-POLG-GFP/BFP Day 0 DN-POLG-GFP/BFP Day 3 DN-POLG-GFP/BFP Day 6 DN-POLG-GFP/BFP Day 9 DN-POLG-AOX/NDI1 Day 0 DN-POLG-AOX/NDI1 Day 3 DN-POLG-AOX/NDI1 Day 6 DN-POLG-AOX/NDI1 Day 9 Amino Acid Carbohydrate Cofactors and Vitamins Energy Lipid Nucleotide Peptide Xenobiotics

29 Study of the metabolic profile of the cells

30 AOX-NDI expression maintains levels of TCA cycle metabolites.

31 AOX-NDI does NOT restore mitochondrial membrane potential.

32 NDI/ AOX H2OH2OO2O2 ATP 4- ADP 3- AOX-NDI1 expression restores electron flux (TCA cycle) but not membrane potential.  TCA Metabolites NADH/FADH2 NAD + /FAD

33 Is electron flux (TCA cycle) sufficient to restore cell proliferation and histone acetylation?

34 Electron flux (TCA cycle) is sufficient to restore histone acetylation. 0369 DN-POLG-AOX/NDI1 DOX - + + + Days H3K14ac H3 total H3K9ac H3K27ac H3K18ac

35 Electron flux (TCA cycle) is NOT sufficient to restore cell proliferation.

36 Electron flux (TCA cycle) is NOT sufficient to restore increased glucose catabolism.

37 Electron flux (TCA cycle) is NOT sufficient to restore glucose dependency for survival.

38 DOX Days AMPK p-AMPK Actin - - + + + + + + 0 0 3 3 6 6 9 9 DN-POLG-AOX/NDI1 Electron flux without proton pumping is NOT sufficient to alleviate energetic stress.

39 H+H+ ETC H2OH2O O2O2 H+H+ ADP ATP H+H+ TCA Two functions of mitochondria: TCA cycle metabolites and membrane potential. Cell Proliferation  ? Histone Acetylation NADH/FADH2 NAD + /FAD

40 AcknowledgementsCollaborators He Huang Yingming Zhao Ty Wang Janine Santos Eric Dufor Hans Spelbrink Ralph Deberardinis Chandel Lab Nav Chandel Sam Weinberg Heywon Kong Lauren Diebold James Eisenbart Manan Metha Colleen Reczek Arianne Rodriguez Michael Schieber

41 Loss of ATPIF1 allows the maintenance of mitochondrial membrane potential

42 Loss of mitochondrial DNA decreased mitochondrial mass.

43 Loss of mitochondrial DNA alters mitochondrial morphology

44

45 Let Us Meet Again We welcome you all to our future conferences of OMICS International Please Visit: w w.metabolomicsconference.com w.conferenceseries.com http://www.conferenceseries.com/clinical-research- conferences.php


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