MiPsummer Programme pdf - Mitochondrial Physiology Society

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54 Mitochondrial Dysfunction and Oxidative Stress in Naturally-Occurring Feline Hypertrophic Cardiomyopathy L. Christiansen 1 , Flemming Dela 2 , Jørgen Koch 1 , and Takashi Yokota 2 Abstract # 25 1 Department of Veterinary Clinical and Animal Science, University of Copenhagen, Faculty of Health Sciences, Dyrlægevej 16, 1870 Frederiksberg; 2 Center for Healthy Aging, Department of Biomedical Sciences, University of Copenhagen, Faculty of Health Sciences, Blegdamsvej 3B, 2200 Copenhagen N E-mail: lbc@sund.ku.dk Background: Hypertrophic cardiomyopathy (HCM) is a primary myocardial disease, characterized by unexplained hypertrophy of the left ventricle. HCM features similar clinical and pathological characteristics in human beings and cats. Mitochondrial dysfunction and oxidative stress are well known to play a role in heart failure and in various cardiovascular diseases. However, in the pathogenesis of naturally occurring HCM, the role of mitochondrial function and oxidative stress is not known. Objectives: The study aimed at evaluating the involvement of mitochondrial dysfunction in naturallyoccurring feline HCM before severe heart failure develops. Methods: Cardiac muscle was obtained from nine cats diagnosed with HCM (6 males; 2-10 years old, 6.6 ± 0.8 (mean ± SEM)) and from fifteen age-matched control cats (CON) (4 males; 2-11 years, 4.9 ± 0.7). Highresolution respirometry was used to measure mitochondrial function in permeabilized, cardiac muscle fibres. Oxidative stress was assessed by measurements of mitochondrial H 2 O 2 generation and thiobarbituric acid reactive substances (TBARS). Results: In heart muscle of HCM cats, complex-I-linked state 3-respiration was significantly decreased (30 ± 6 pmol s -1 mg -1 ) compared to CON (65 ± 7 pmol s -1 mg -1 ) (P=0.002). Fatty acid oxidation with palmitoylcarnitine and octanoyl-carnitine was significantly decreased in HCM hearts (12 ± 2 pmol s -1 mg -1 ) and (15 ± 1 pmol s -1 mg -1 ) compared to CON (30 ± 2 pmol s -1 mg -1 ) and (45 ± 5 pmol s -1 mg -1 ), respectively (P=0,002 and P=0.0001). Mitochondrial H 2 O 2 generation during state 3, with complex I-linked substrates, was significantly higher in HCM hearts compared to CON (P
55 Abstract # 26 Myocardial Fatty Acid Oxidation is Regulated by CD36-Mediated FA F Signalingg TA Pietka, D Samovski, J Sun, K Yang, B Aldridge, RW Gross, PD Stahl, NA Abumrad Washingtonn University School of Medicine, St. Louis, Missouri, USA Background: The multifunctional scavenger s receptor CD36 facilitates cellular long chain fatty acid (FA) uptake and mediates FA-related intracellular signaling. The CD36-defici ent (CD36KO) heart, fed or fasted utilizes less palmitate and more glucose indicating impaired fuel flexibility (1, 2) andd we recently showed that CD36KO mice subjected to an overnight fast develop electrical abnormalities and altered lipid metabolismm (3). Objectives: We hypothesized that FA-signaling g via CD36 at the plasma membrane plays a key role in regulating fatty acid oxidation and investigated the impact of altered acylcarnitine production in the t CD36 deficient heart. Methods: Acylcarnitine content was determinedd in fasted wild-type (WT) and CD36KO hearts using multidimensional shotgun lipidomics. OXPHOSS capacity and protein content of respiratory complex subunits were measured in isolated mitochondria a from WT and CD36KOO hearts. Palmitate induced activation of AMP kinase (AMPK, p-T172) protein was measured in control and CD36 knockdown C2C12 myotubes and fasted WT and CD36KO mouse hearts by western blotting. Finally, palmitate induced oxidation was measured in intact and saponin-permeabilized soleus muscle fibers from wild-type mice. Results: Consistent with the known impairment of FA oxidation in the fasted CD36KO heart (1, 2), we found that the fasted CD36KO heartt is deficient in the ability to increase acylcarnitine production. Additionally, there were no defects in mitochondrial oxidative capacityy or respiratory chain protein subunits in myocardial mitochondria from the CD36KOO mouse compared to wild-type. Interestingly, despite the lack off increased FA oxidation or acylcarnitine production, CD36 deficiency increased basal levels and activation of AMPK in the heart. h Similar results were found with CD36 knockdown C2C12 cells, which had a higher basal activation of AMPK that was unresponsive to the palmitate induced activation of AMPK observed inn control C2C12 cells. Thus, the lack of FA oxidation in the fasted CD36 deficient heart likely reflects a limiting role of plasma membrane-mediated FA supply and deficient FA-induced signaling and iss not due to insufficient AMPK activation. To test this theory, O2 consumption induced by palmitate oxidation was measured in intact and saponin-permeabilized wild-type mouse soleus muscle m fibers. We found that permeabilization resulted in a ~50% decrease in respiration (Figure), indicating that FA induced uptake/signaling at the plasma membrane drivess FA oxidation. Conclusion: Fatty acid binding to CD36 triggerss intracellular signaling events e that ultimately lead to activation of AMPK and results in enhanced fatty acid oxidation. References: 1. Coburn, C.T., Knapp, F.F., Jr., Febbraio, M., Beets, A.L., Silverstein, R.L., and Abumrad, N.A. 2000. Defective uptake and utilization of long chain fatty acids in muscle and adipose tissues of CD36 knockout mice. J Biol Chem 275:32523-32529. 2. Nahle, Z., Hsieh, M., Pietka, T., Coburn, C.T., Grimaldi, P.A., Zhang, M.Q., Das, D D., and Abumrad, N.A. 2008. CD36-dependent regulation of muscle FoxO1 and PDK4 in the PPAR delta/beta-mediated adaptation to metabolic stress. J Biol Chem 283:14317-14326. 3. Pietka, T.A., Sulkin, M. .S., Kuda, O., Wang, W., Zhou, D., Yamada, K.A., Yang, K., Su, X., Gross, R.W., Nerbonne, J.M., et al. 2012. CD36 protein influences myocardial Ca2+ homeostasis and phospholipid metabolism: conduction anomalies in CD36-deficient mice during fasting. J Biol Chem 287:38901-38912.
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COPENHAGEN MiP SUMMER 2013 MITOCHON
Page 3 and 4: 3 MiPs - The Mitochondrial Physiolo
Page 5 and 6: 5 Finding your way at the Panum Ins
Page 7 and 8: 7 PANUM INSTITUTE HOTEL ØSTERPORT
Page 9 and 10: 9 Afternoon programme Monday 26th A
Page 11 and 12: 11 Poster walk/talk The poster sess
Page 13 and 14: 13 Overview of workshops Tuesday, A
Page 15 and 16: 15 Overview of workshops Thursday,
Page 17 and 18: 17 Participants Adelheid Weidinger
Page 19 and 20: 19 Participants Giulia Girolimetti
Page 21 and 22: 21 Participants Michel van Schaarde
Page 23 and 24: 23 Speakers Albert Gjedde Universit
Page 25 and 26: 25 Organizers & teachers Bjørn Qui
Page 27 and 28: 27 Abstract # 1 Nicotinamide phosph
Page 29 and 30: 29 Abstract # 3 Aerobic interval tr
Page 31 and 32: 31 Abstract # 5 The progressive eff
Page 33 and 34: 33 Abstract # 7 Exercise with low g
Page 35 and 36: 35 Tuesday 27 th Aging, Development
Page 37 and 38: 37 Abstract # 10 Overexpression of
Page 39 and 40: 39 Abstract # 12 Physical Propertie
Page 41 and 42: 41 Abstract # 14 MITOCHONDRIAL RHOM
Page 43 and 44: 43 Tuesday 27 th Neuro Abstracts #
Page 45 and 46: 45 Abstract # 17 Mitochondrial comp
Page 47 and 48: 47 Abstract # 19 Over Expression of
Page 49 and 50: 49 Abstract # 21 Flux control analy
Page 51 and 52: 51 Abstract # 23 Developing models
Page 53: 53 Abstract # 24 Reperfusion-induce
Page 57 and 58: 57 Time dependence of diet-induced
Page 59 and 60: 59 Thursday 29 th Models, Structure
Page 61 and 62: 61 Abstract # 31 Generation of a Dr
Page 63 and 64: 63 Abstract # 33 The human N-termin
Page 65 and 66: 65 Abstract # 35 Mitochondrial memb
Page 67 and 68: 67 Thursday 29 th Inflammation, Oxi
Page 69 and 70: 69 Abstract # 38 Evidence that fibr
Page 71 and 72: 71 Abstract # 40 Linking placental
Page 73 and 74: 73 Abstract # 42 CVB3-induced oxida
Page 75 and 76: 75 Abstract # 43 Metabolic flexibil
Page 77 and 78: 77 Abstract # 45 Dietary restrictio
Page 79 and 80: 79 Abstract # 47 Insulin sensitivit
Page 81 and 82: 81 Abstract # 49 Mitochondrial toxi
Page 83 and 84: 83 Altered mitochondrial DNA conten
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