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Slide 2 Loomis & Lipmann Slide 3 m = 4 kcal/mol m = 12 kcal/mol Slide 4 Mitochondrial uncoupling is physiologically mediated by uncoupling proteins Slide 5 Mecanismo de Produo de Calor pelo Tecido Adiposo Marrom Termografia do infravermelho emitido pela superfcie dorsal de um rato com uma semana de vida. O ponto amarelo "quente" se sobrepe ao depsito de BAT. Slide 6 Brown adipose tissue is rich in mitochondria and uncoupling protein 1 Slide 7 Termognese independente de contrao muscular Tecido Adiposo Branco-WAT pouco vascularizado poucas mitocndrias x132 Tecido Adiposo Marrom-BAT altamente vascularizado muitas mitocndrias BAT (Tecido Adiposo Marrom) Mamferos hibernantes Pequenos mamferos Mamferos jovens (incluindo humanos) Adapato ao frio Slide 8 Slide 9 Responsiveness of BAT related to gender and age Slide 10 Slide 11 BAT activity contributes to energy expenditure in adult humans Slide 12 Methamphetamine-induced malignant hyperthermia are mediated by mitochondrial uncoupling Pharmacology: uncoupling the agony from ecstasy. Mills EM, Banks ML, Sprague JE, Finkel T. Nature. 2003 Nov 27;426(6965):403-4. Slide 13 Mitochondrial uncoupling reduces insulin secretion in pancreatic beta cells Slide 14 Slide 15 Energy from electrons flow generates heat in plants !!! Roger Seymour University of Adelaide Australia Slide 16 Heat generation in thermogenic plants depends on the increase of oxygen consumption Slide 17 Heat generation in thermogenic plants depends on the increase of oxygen consumption Slide 18 Slide 19 A long time ago in a galaxy Not so far away... Slide 20 Mitochondria may allow multicellular organization through increased the energy efficiency Slide 21 Meganeura sp. Carboniferous gigantism is related to increased atmosferic levels of oxygen Slide 22 Slide 23 A encruzilhada dos anaerbicos... Slide 24 Exposio O 2 100% causa leso pulmonar Slide 25 Oxignio possui eltrons desemparelhados Slide 26 Slide 27 Slide 28 Free radicals Atoms or molecules that have at least one unpaired electron. Reach equillibrium donating or removing na electrons from the nearest molecule. Highly reactive species ! Slide 29 Reactive oxygen species (ROS) Derived from molecular oxygen Free radicals superoxide, O 2 - Hydroxyl radical, OH Peroxyl radical, ROO Alkoxyl radical, RO Hydroperoxyl radical, HO 2 Non-radical reactive oxygen species Hydrogen peroxide, H 2 O 2 (Fentons reaction) Hypochlorous Acid, HClO Ozone, O 3 Slide 30 Free radical theory of aging AGING - A THEORY BASED ON FREE-RADICAL AND RADIATION-CHEMISTRY HARMAN, D. JOURNALS OF GERONTOLOGY, 11, 3, 298-300 Slide 31 Evidence 1) Longer lived species exhibit decreased levels of oxidative damage, decreased susceptibility to oxidative stress, and decreased generation of reactive oxygen species. 2) Results have demonstrated that the overexpression of catalase, increased both the average lifespan and maximum lifespan of mice by 20%. 3) Mutant strains of Caenorhabditis elegans that are more susceptible to free radicals have shortened lifespans, and vice versa. 4) Drosophila that have mutations in enzymes relating to reactive oxygen species metabolism have also been shown to have dramatically reduced life-spans, increased susceptibility to oxidative stress and ionizing radiation, partial female and complete male sterility. 5) Antioxidant supplementation has not been conclusively shown to produce an extension of lifespan in a mammal. Free radical theory of aging AGING - A THEORY BASED ON FREE-RADICAL AND RADIATION-CHEMISTRY HARMAN, D. JOURNALS OF GERONTOLOGY, 11, 3, 298-300 Slide 32 Slide 33 Mitochondria represent one of the major sources of ROS/RNS Slide 34 Slide 35 ROS A gerao das ROS depende do estado metablico da mitocndria Mitochondrial ROS generation depends of m Slide 36 The good side of free radicals a massive production of ROS as immunity instrument Leukocytes Macrophages Lymphocytes Myeloperoxidase = hypochlorpous acid NADPH oxidase = superoxide Bernard Babior BIOLOGICAL DEFENSE MECHANISMS - PRODUCTION BY LEUKOCYTES OF SUPEROXIDE A POTENTIAL BACTERICIDAL AGENT. BABIOR, BM; KIPNES, RS; CURNUTTE, JT. JOURNAL OF CLINICAL INVESTIGATION, 52, 3, 741-744 Slide 37 Oxidative damage to lipids Damage unsaturated bonds loss RONS metabolites generation (aldehydes) Sequel changes in fluidity and permeability of membranes (cell lysis) membranes integral enzymes are influenced Slide 38 Oxidative damage to proteins Damage agregation, fragmentation and cleveage reaction with heme iron functional group modification Sequel changes in enzyme activity Proteolysis Aggregation Slide 39 Oxidative damage to DNA Damage saccharide ring cleveage base modification chain breakeage Sequel mutation translation mistakes Protein synthesis inhibition Slide 40 Oxidative stress Equilibrium failure between generation and removal of ROS / RNS leads to Slide 41 Antioxidant defenses Preventives Inhibit ROS/RNS generation Scavengers Scavenge unpaired ROS/RNS electrons Repair Correct molecules damaged by ROS/RNS Slide 42 Antioxidants and scavengers enzymes Superoxide dismutase, Catalase, Glutathione peroxidase nonenzymatic a) fixed in membranes ( -tocopherol, -carotene) b) out of membranes (ascorbate, transferrin, bilirubin) Slide 43 Antioxidant enzymes in mitochondria [ O 2 ] - H2O2H2O2 SOD CATALASE H 2 O + O 2 Fe 2+ Fenton reaction OH. + Fe 3+ + OH - GPx 2 H 2 O 2GSH GSSG GR NADPH.H + NADP + Slide 44 Low-molecular weigth antioxidants I Ascorbate (vitamin C) a)Important antioxidant in extra and in intracellular compartments b)Present in aqueous environments c)Reduces O 2 , - OH , ROO, RO Slide 45 Low-molecular weight antioxidants II -tocopherol (vitamin E) a) Membrane associated antioxidant b) Stored mainly in the adipose tissue, the liver and in muscles, the principal role of vitamin E is as a powerful antioxidant, protecting body cells from the detrimental effects of free radicals and protecting unsaturated lipids against oxidation. Slide 46 Low-molecular weight antioxidants III Glutathione a) Tripeptide present in all mammalian cells (SH group) b) Important redox buffer (2 GSH GSSG + 2e - + 2H + ) c) ROS elimination, stabilisation in reduction form (SH-groups, tocopheryl and ascorbate regeneration) d) Substrate of glutathione peroxidases Slide 47 Slide 48 Parkinsons Disease & ROS Slide 49 Slide 50 Slide 51 Slide 52 Slide 53 Slide 54 Slide 55 Slide 56