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OXYGEN RADICALSand AGING
Rondang R. Soegianto
2009
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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 are
catalyzed 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 coenzymeB Flavin as coenzyme
C Cytochromes (Fe-porphyrin as coenzyme)
3. Hydroperoxidases:
A PeroxidaseB 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 inmitochondria
B. Flavoproteins, contain FMN or FAD
Ex. : L-aminoacid oxidase
Xanthine oxidaseAldehyde dehydrogenase
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3. Hydroperoxidases use H2O2as 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
Peroxidase
Gluthatione peroxidase
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B. Catalase
Hemoprotein 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 + OCatalase22 2
-2
-2 + 2 2SOD
2 2
2
- 2 2 -
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Mitochondria
Make > 90% of cellular ATP
Powerplant of the cell
Four Compartments
Matrix has numerous enzymes that reduceNAD+to NADH during catabolism of foodstuffs
Inner Membrane has:
Proteins that transfer electrons (the ETS)
ATP synthase
Intermembrane Space
Outer 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 ATP
Harper 26 Fig. 12-2
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Harper 26 Fig. 12-4
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Reactive Oxygen Species (ROS) are
oxygen radicals that may cause damage
to 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 ofMatrix 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) proteins
These have to be eliminated (degradation)
With aging: Disturbed balance betweenaccumulation and degradation of
modified forms.
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Other type of age associated modification:
Protein Glycosylation
(non enzymatic)
Causes aging of long lived proteins
Such as: Collagen
Crystallin
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Glycosylation = Maillard reaction
Addition of carbohydrate to protein
Normally for protein secreted by cellor protein bound to cell surface
Hb can be glycosylated in blood glucose
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Final products of glycosylaton called
Advanced Glycosylation Endproducts (AGE)
Free radicals induce formation andaccumulation of AGE
ANTIOXIDANTS inhibit protein glycation
And accumulation of AGE
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With increasing age and glucoseconcentration
accumulation of AGE in plasmaand vessel walls
cause many diabetic complications(cataract, atherosclerosis)
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Other type of protein modification due
to 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 capacity
of cells and tissues during aging
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Caloric Restriction (CR)
Since major endogenous source of ROS
is 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