oxygen radicals & aging
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*OXYGEN RADICALS and AGING Rondang R. Soegianto2009
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*Oxidative Damage and Aging are
two processes commonly found
in eukaryotic organisms
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*ENERGY, essential for life processes
In humans,
Electron Transport System (ETS) in
mitochondria is main mechanism for aerobic energy supply
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*ATP = Energy currency of the cell
Produced in mitochondria via
Oxidative Phosphorylation (OXPHOS)
Oxidation processes in living systems arecatalyzed by class I enzymes: OXIDOREDUCTASES
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Oxidoreductases (Harper 26th)
1. Oxidases: A Containing Cu B As flavoproteins
2. Dehydrogenases: A. NAD+ or NADP+ as coenzyme B Flavin as coenzyme C Cytochromes (Fe-porphyrin as coenzyme)
3. Hydroperoxidases: A Peroxidase B Catalase 4. Oxygenases: A Dioxigenase B Monooxigenase
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*1. Oxidases: - Remove 2 protons (H+) from substrate and pass to oksigen - Generate H2O or H2O2 Two groups of oxidases: A Containing Cu Example: Cytochrome a3 (cyt a3) also known as cyt aa3 Is a cytochrome oxidase Terminal compound of the respiratory chain in mitochondria B. Flavoproteins, contain FMN or FAD Ex. : L-aminoacid oxidase Xanthine oxidase Aldehyde dehydrogenase
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*Hydroperoxidases use H2O2 as substrate
A. Peroxidase reduces peroxides using various e- acceptors H2O2 + AH2 2 H2O + A
In erythrocytes and other tissues:
H2O2 + 2 GSH GSSG + H2O GSH = Reduced gluthatione Glutamyl-cysteinyl-glycine (a tripeptide) -SH = Reducing group of cysteine residue
PeroxidaseGluthatione peroxidase
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*CatalaseHemoprotein with 4 heme groups
2 H2O2 2 H2O + O2
Found in: Blood, bone marrow, mucous membranes Kidney, liver Catalase destroys peroxides formed by oxidases
Catalase
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*Free radicals
Transfer of a single e to O O (superoxide anion)Can damage membranes, DNA, etc.
Destructive effects Amplified by: Free radical chain reaction Removed by: Superoxide dismutase (SOD) in the reactions
O + O 2H H O + O
H O 2H O + O
Catalase222 -2 -2+22SOD222- 22 -
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*Mitochondria Make > 90% of cellular ATPPowerplant of the cell Four CompartmentsMatrix has numerous enzymes that reduce NAD+ to NADH during catabolism of foodstuffsInner Membrane has:Proteins that transfer electrons (the ETS)ATP synthaseIntermembrane SpaceOuter Membrane
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*Faces of mitochondrial membrane (V & V Fig. 20-3)
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Role of RC of mitochondria in the conversion of food energy to ATPHarper 26 Fig. 12-2
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*Harper 26 Fig. 12-4
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*Reactive Oxygen Species (ROS) areoxygen radicals that may cause damageto cells and tissues, such as in- Neurodegenerative diseases (Alzheimer, Parkinson)
Cardiovascular diseases
- Rheumatoid Arthritis (RA) (Bone erosion, cartilage loss, loss of joint function)
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*In RA :
ROS does not destroy collagen directly
ROS induces synthesis of Matrix Metalloproteinase (MMP)
that attacks connective tissues Therapy targeted at possible MMP inhibitors
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*Effect of ROS ona. Lipid and Nucleic Acids Double bonds, easy target for oxidative damage (lipid peroxidation) b. Cellular protein and Enzymes Oxidation produces altered proteins
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*Altered proteins accumulate with aging.
This will interfere with normal homeostasis
Can cause age related pathologies, such as- Atherosclerosis- Senile cataract- Diabetes Mellitus- Immune system failure- Neurodegenerative diseases
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*Age related changes in enzymes and other proteins:
- Alteration in catalytic activities- Altered folding in the 3-D structure
The products are altered (abnormal) proteinsThese have to be eliminated (degradation)
With aging: Disturbed balance betweenaccumulation and degradation ofmodified forms.
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*Other type of age associated modification:
Protein Glycosylation (non enzymatic)
Causes aging of long lived proteinsSuch as: Collagen Crystallin
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*Glycosylation = Maillard reaction
Addition of carbohydrate to proteinNormally for protein secreted by cellor protein bound to cell surface
Hb can be glycosylated in blood glucosewith the formation of HbA1c
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*Inactivation by glycosylation occursin proteins with lysine in critical location
SuperoxydedismutaseRibonucleaseNa+, K+-ATPase
Experimentally inactivated whenincubated in glucose
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*Final products of glycosylaton called
Advanced Glycosylation Endproducts (AGE)
Free radicals induce formation and accumulation of AGE
ANTIOXIDANTS inhibit protein glycation And accumulation of AGE
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*With increasing age and glucose concentration
accumulation of AGE in plasma and vessel walls
cause many diabetic complications (cataract, atherosclerosis)
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*Other type of protein modification dueto oxidative stress is
formation of protein-protein Cross Links
caused mainly by disulfide bonds
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*Mitochondrial Dysfunction
ROS generated during aging Chronic oxidative damage to Electron Transport System (ETS)
Resulting decrease in functional capacityof cells and tissues during aging
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*Caloric Restriction (CR)
Since major endogenous source of ROSis mitochondrial respiration,
CR markedly reduces production of Superoxide and H2O2
Effect of CR most striking in brain
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*Kristal and Yu (1992)
Age related deterioration is produced
by the sum of the damage induced by
free radicals, by glycation (Maillard reaction)and by their interactions.
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*Reference:
OXYGEN RADICALS and the
DISEASE PROCESS
Thomas, C.E., Kalyanaraman, B. eds
Harwood academic publishers