LECTURE-5 - Outline Adaptations of Free Radical Biology to...

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Adaptations of “Free Radical Biology” to Acute and Chronic Exercise Slide Contributed by: Dr. Leeuwenburgh Dr. Neiss Sharon Phaneuf Outline 1. Mitochondrial production of oxidants during acute exercise 2. Production of oxidants by xanthine oxidase during exhaustive exercise 3. Exercise, Muscle Injury (Delayed Onset Soreness) Inflammation and Oxidative stress. Inflammation and production of oxidants by oxidases 4. Exercise Training and Longevity in Animals and Humans 5. Adaptations and Mechanisms with Exercise Training; Potential benefits as countermeasures to aging 6. Exercise and Physical Activity; Effects on Longevity in Humans 7. Reactive Oxygen Species and effects on muscle contractility (brief) 8. Exercise as a model to study cell signaling (brief) Suc inate DH FeS Cyt c1 Cyt a1 Cyt a3 Cyt b NADH CoQ reductase complex O 2 ·O 2 - O 2 H 2O 4 H + e - e - NAD NADH+e - Krebs cycle CoQ Exercise-induced ROS formation - Potential Sources - ROS AMP IMP hypoxanthine xanthine oxidase xanthine xanthine oxidase uric acid · O 2 - · O 2 - O 2 O 2 NADPH NADPH oxidase NADP + O 2 · O 2 - Fe 2+ + H 2 O 2 · OH + OH - + Fe 3+ Fenton reaction Overview Reactive oxygen species (ROS) - good or bad guys ? ROS Oxidative stress Oxidative damage Cell function Cell death Antioxidant enzymes Stress proteins Cellular redox state Contractile force Redox-sensitive signaling pathways Gene expression (Training-) adaptation H + FeS N-2 cyt c I I CuB a a3 Q0 Qi bb FeS C1 SDH cyt c CoQ Reactive Oxygen species and the Respiratory Chain NADH Succinate Complex I Complex II Complex III Complex IV O 2 O 2 - H 2 O 2 SOD2 IMS SOD1 H 2 O 2 O 2 O 2 - MATRIX Melov S. PhD
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Generation of Radicals: Main Source Mitochondrial respiratory chain (‘Electron Transport Chain’) e.g. superoxide radical; H 2 O 2 , hydroxyl radical ; More Oxygen More Radicals?? “Radical” Reactions O 2 + e <=> O 2 - Equation 1 O 2 + 2e + 2H + H 2 O 2 Equation 2 O 2 - + O 2 - + 2H + SOD H 2 O 2 + O 2 Equation 3 H 2 O 2 + 2GSH GPX H 2 O + GSSG + ROH Equation 4 2H 2 O 2 + Catalase 2H 2 O + O 2 Equation 5 Fe 2+ + H 2 O 2 HO + HO - + Fe 3+ Equation 6 O 2 - + NO ONOO - Equation 7 O 2 - +M n+ O 2 + M (n-1)+ Equation 8 MITOCHONDRIAL OXYGEN RADICAL GENERATION & LEAK: SITES OF PRODUCTION IN STATES 4 & 3, Gustavo Barja Journal of Bioenergetics & Biomembranes. 31:4:1999 Background: • What are mechanisms to reduce radical production during acute exercise? • Comparing data from isolated mitochondria with the hypothetical in vivo (“physiological exercise”) situation. • Keep in mind!!! – Oxygen tension – State 3 vs. State 4 – Tissue specificity!!! i.e.Heart vs. Muscle Quantification of radical generation via: 1. Substrate Type (‘fuel’) 2. “Stress” on mitochondria (rest vs active state) Generation of Radicals • Mitochondrial Stress: I.Resting (substrate only) STATE 4 II.Active (substrate + ADP) STATE 3
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Mitochondrial Respiratory Chain RESULTS: STATE 4 (resting) • COMPLEX I +/or III - contain O 2 radical generator(s) • Pyr/Mal as substrate produce H 2 O 2 than Succinate
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LECTURE-5 - Outline Adaptations of Free Radical Biology to...

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