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Welcome to MMIG ( Mitochondria and Metabolism Interest Group )

Welcome to MMIG ( Mitochondria and Metabolism Interest Group ). What is MMIG?. Interest-driven group open to all PIs studying M & M, currently ~25 members Scientific exchange and collaboration Share resources and expertise Strengthen training environment Program development and visibility.

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Welcome to MMIG ( Mitochondria and Metabolism Interest Group )

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  1. Welcome to MMIG(Mitochondria and Metabolism Interest Group)

  2. What is MMIG? • Interest-driven group open to all PIs studying M & M, currently ~25 members • Scientific exchange and collaboration • Share resources and expertise • Strengthen training environment • Program development and visibility

  3. Format • Regular meetings: weekly, biweekly or monthly? • Invited speakers/visitors (local and national): Monthly? • Forum for the trainees (journal club and work-in-progress presentations) • Annual retreat: November 8-9, 2010

  4. Home base: Mitochondria and Metabolism Center at SLU http://depts.washington.edu/mmcslu • Program Specialist: Karen Liebertmmcslu@u.washington.edu • Refer new MMIG members • Suggest future meeting place • Suggest speakers, meeting time and frequency

  5. gas-1 clk-1 mev-1 isp-1 ctb-1 Mitochondrial Mutants MMIG - 9 June 2010 - Morgan/Sedensky 1

  6. Affected complex in kids? MMIG - 9 June 2010 - Morgan/Sedensky 2

  7. Respiratory Supercomplexes in C. elegans MMIG - 9 June 2010 - Morgan/Sedensky 3 (Suthammarak et al, JBC 2008)

  8. The complexities of regulating mitochondria in neurons How is mitochondrial dynamics (fission/fusion) regulated in neurons? Is the fission/fusion machinery in neurons unique? How is mitochondrial fission/fusion regulated in neurons in response to injury and disease? Can we prevent neuronal apoptosis and maintain function by modulating mitochondrial dynamics? MMIG - 9 June 2010 - Morrison 1

  9. MMIG - 9 June 2010 - Morrison 2

  10. MMIG - 9 June 2010 - Morrison 3

  11. Wang lab Research interests: • Physiological mitochondrial permeability transition pore (mPTP) opening and superoxide flash activity in the heart; • Molecular mechanism of mPTP triggered superoxide flash production; • Role of mitochondrial reactive oxygen species (ROS) in oxidative stress. What we do? • Focus on cardiovascular system; • Adult cardiac myocyte culture and adenovirus mediated gene transfer; • Confocal measurement of superoxide flash (cpYFP), mitochondrial / cytosolic Ca2+ and mitochondrial membrane potential; • Assessment of cardiac myocyte function: contractility & Ca2+ handling; • Transgenic mice expressing superoxide indicator in mitochondria; • Mitochondrial ROS signaling in disease: ischemia reperfusion injury, heart failure, diabetes and metabolic syndrome. MMIG - 9 June 2010 - Wang 1

  12. Single Mitochondrial Superoxide Flash in Adult Cardiac Myocyte 10 m Time (s) 488 nm 405 nm TMRM 0.3 F/F0 488 nm 0.5 F/F0 10 s 405 nm 488 nm 20 s 405 nm MMIG - 9 June 2010 - Wang 2 (Wang et al, 2008, Cell 134:279-290)

  13. Integrative Study of Mitochondrial Function in Health & Disease MMIG - 9 June 2010 - Wang 3 https://depts.washington.edu/mmcslu/home

  14. PLC How do mitochondria produce ROS? How are mitochondrial ROS ‘decoded’? IP3 DAG PKC Apoptosis Ca Dymloss Ca Ca Ca Ca Ca Ca Ca IP3R Ca Ca Ca Ca Ca Ca TCA Ca Ca Ca Ca Ca Ca Ca Ca Ca Ca ROS Ca Ca Ca Ca Bioenergetics Ca Ca Ca Ca Ca Ca NF-kB Ca Ca Ca Ca Ca Ca Inflammation Ca MMIG - 9 June 2010 - Hawkins 1

  15. Relationship between cytosolic calcium and mitochondrial ROS ROS MMIG - 9 June 2010 - Hawkins 2

  16. Laboratory Interests • How do disparate mitochondrial calcium uptake patterns translate to cellular function? • How do calcium-linked oxidants influence mitochondrial function? • What are the cellular targets of mitochondrial reactive oxygen species? Microvascular EC Macrovascular EC MMIG - 9 June 2010 - Hawkins 3

  17. Mitochondrial hub in apoptosis Smart bombs MMIG - 9 June 2010 - Hockenberry 1

  18. Metabolic functions of oncogenes Myc Bcl-XL MMIG - 9 June 2010 - Hockenberry 2

  19. Hsp90 and proteasome - dependent degradation of mitochondrial proteins (an ERAD-like pathway) Mitochondrial graveyard or nursery MMIG - 9 June 2010 - Hockenberry 3

  20. oxy deoxy nm PCr Pi ATP ppm PCr MbO2 ATP HbO2 NMR OPTICS OPTICS MMIG - 9 June 2010 - Marcinek 1

  21. Less Efficient Mitochondria in Aged Muscle H+ H+ H+ O2 H2O ATP ATP production O2 consumption * P/O * 7-month 30-month MMIG - 9 June 2010 - Marcinek 2 Marcinek et al., 2005, J Physiol, 569

  22. Control of Mitochondria by Oxidative Stress 2 wk PQ 7 mo SOD1-/- mTOR signaling, muscle atrophy, aging apoptosis, mitochondrial biogenesis Implications: MMIG - 9 June 2010 - Marcinek 3

  23. Joachim Voss, PhD, RN, Assistant ProfessorRWJ Nurse Faculty FellowSchool of Nursing HIV-related Fatigue and Mitochondrial Dysfunction related to Antiretroviral Treatments MMIG - 9 June 2010 - Voss 1

  24. Projects • Proteomic Biomarker Discovery in Plasma of HIV Patients (Dave Goodlett, School of Pharmacy) • Mitochondrial Function in skeletal muscle of men with prostate cancer-related fatigue • Mitochondrial Dysfunction and NRTI-treatment effects in skeletal muscle of aging mice (Dave Marcinek, Peter Rabinovitch, School of Medicine) • Gene expression changes in skeletal muscle of aging mice receiving antiretroviral treatment for 8 weeks (Molecular Lab in the SON) MMIG - 9 June 2010 - Voss 2

  25. Preliminary Results • Inner mitochondrial membrane proteins in the plasma of patients with HV-related fatigue • Steroid hormone pathway is impacted by HIV and ART treatment • PGC1α and Thymidine kinase 2 are affected by AZT treatment • Significant changes in ATP production with AZT treatment MMIG - 9 June 2010 - Voss 3

  26. CLINICAL TRIALS - FDA • THYROID HORMONE SUPPLEMENTATION IN INFANTS UNDERGOING CARDIOPULMONARY BYPASS (FDA) • MULTI-SITE • RECRUITED 200 PATIENTS… • ONE OF THE LARGEST CLINICAL TRIALS EVER PERFORMED IN PEDIATRIC CARDIOLOGY/CARDIAC SURGERY • T3 SUPPLEMENTATION IMPROVED CLINICAL ENDPOINTS AND CARDIAC FUNCTION IN INFANTS MMIG - 9 June 2010 - Portman 1

  27. MECHANISMS FOR CLINICAL RESPONSE: ANIMAL MODELS OF PEDIATRIC MECHANICAL-CIRCULATORY SUPPORT T3 NiOx MMIG - 9 June 2010 - Portman 2

  28. AGING • Dominant negative thyroid hormone receptoralters substrate metabolism with reduction in FFA flux • Aging in mice results in reduced FFA flux with decreased systolic function • T3 reduced in aging mouse model Hypothesis - T3 treatment modifies substrate flux and restores cardiac function MMIG - 9 June 2010 - Portman 3

  29. Tian Lab studies the Heart Cardiac metabolism and Energetics: Modulating cardiac energy metabolism to improve cardiac function during stresses – Transgenic mice and NMR Mitochondrial Biogenesis and Function: Regulation of mitochondrial biogenesis in heart failure -- mtDNA replication Mechanistic link between mito dysfunction and the development of pathological hypertrophy Metabolic Signaling: AMPK-activated Protein Kinase (AMPK): Signaling cascade and isoform-specific roles of AMPK in the heart Metabolites regulate cardiac biology: integrating transcriptomics with metabolomics MMIG - 9 June 2010 - Tian 1 Tian

  30. Functional and Metabolic Phenotyping 13C NMR Spectroscopy Transgenic Mice TAC or MI Langendorff Perfusions In vivo Cardiac function 31P NMR Spectroscopy mixed substrates 5.5mM 1,6-13C GLU 0.4mM U-13C FA 1.2mM Lactate 50μU/ml Insulin NMR imaging + localized spectroscopy MMIG - 9 June 2010 - Tian 2 Tian

  31. Pi M∞ endo glucose lactate ketones PCr M0-M∞ fatty acids ATP Kfor = g a T1 M∞ Pi b M0 Flux = Kfor x [Pi] Dynamic changes of myocardial energetics and ATP synthesis in beating hearts by 31P NMR % oxidation of carbon substrate by 13C NMR PPAR-/- WT endo glucose lactate ketones fatty acids PPAR-/-GLUT1 glucose glucose endo ADP + Pi  ATP ketones ketones lactate lactate fatty acids MMIG - 9 June 2010 - Tian 3 Tian

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