Mitochondrial uncoupling is physiologically mediated by uncoupling proteins
Mecanismo de Produção de Calor pelo Tecido Adiposo Marrom Termografia do infravermelho emitido pela superfície dorsal de um rato com uma semana de vida. O ponto amarelo "quente" se sobrepõe ao depósito de BAT.
Brown adipose tissue is rich in mitochondria and uncoupling protein 1
Termogênese independente de contração muscular Tecido Adiposo Branco-WAT pouco vascularizado poucas mitocôndrias x132 Tecido Adiposo Marrom-BAT altamente vascularizado muitas mitocôndrias BAT (Tecido Adiposo Marrom) Mamíferos hibernantes Pequenos mamíferos Mamíferos jovens (incluindo humanos) Adapatção ao frio
BAT activity contributes to energy expenditure in adult humans
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.
Mitochondrial uncoupling reduces insulin secretion in pancreatic beta cells
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 !
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 (Fenton´s reaction) Hypochlorous Acid, HClO Ozone, O 3
Free radical theory of aging AGING - A THEORY BASED ON FREE-RADICAL AND RADIATION-CHEMISTRY HARMAN, D. JOURNALS OF GERONTOLOGY, 11, 3, 298-300
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
ROS A geração das ROS depende do estado metabólico da mitocôndria Mitochondrial ROS generation depends of m
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
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
Oxidative damage to proteins Damage agregation, fragmentation and cleveage reaction with heme iron functional group modification Sequel changes in enzyme activity Proteolysis Aggregation
Oxidative damage to DNA Damage saccharide ring cleveage base modification chain breakeage Sequel mutation translation mistakes Protein synthesis inhibition
Oxidative stress Equilibrium failure between generation and removal of ROS / RNS leads to
Antioxidants and scavengers enzymes Superoxide dismutase, Catalase, Glutathione peroxidase nonenzymatic a) fixed in membranes ( -tocopherol, -carotene) b) out of membranes (ascorbate, transferrin, bilirubin)
Antioxidant enzymes in mitochondria [ O 2 ] - H2O2H2O2 SOD CATALASE H 2 O + ½ O 2 Fe 2+ Fenton reaction OH. + Fe 3+ + OH - GPx 2 H 2 O 2GSH GSSG GR NADPH.H + NADP +
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 ·
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.
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