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OXYGEN RADICALS and AGING

Rondang R. Soegianto 2009


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Oxidative Damage and Aging are


two processes commonly found in eukaryotic organisms

ENERGY, essential for life processes

In humans,
Electron Transport System (ETS) in mitochondria is main mechanism for

aerobic energy supply

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)

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Oxidases:

A Containing Cu B As flavoproteins

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Dehydrogenases: A. NAD+ or NADP+ as coenzyme B Flavin as coenzyme C Cytochromes (Fe-porphyrin as coenzyme) Hydroperoxidases: A Peroxidase B Catalase Oxygenases: A B

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Dioxigenase Monooxigenase

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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 eacceptors
Peroxidase

H2O2 + AH2

2 H 2O + A

In erythrocytes and other tissues: H2O2 + 2 GSH


Gluthatione peroxidase

GSSG + H2O

GSH = Reduced gluthatione Glutamyl-cysteinyl-glycine (a tripeptide) -SH = Reducing group of cysteine residue

B.

Catalase Hemoprotein with 4 heme groups


2 H2O2
Catalase

2 H2O + O2

Found in: Blood, bone marrow, mucous membranes Kidney, liver Catalase destroys peroxides formed by oxidases

Free radicals
- O Transfer of a single e to O2 - (superoxide anion) 2 Can damage membranes, DNA, etc.

Destructive effects Amplified by: Free radical chain reaction Removed by: Superoxide dismutase (SOD) in the reactions
O2 - + O2 2H + SOD

H2 O2 + O2

H2 O2

Catalase

2H2 O2 + O2

Mitochondria

Make > 90% of cellular ATP Powerplant of the cell Four Compartments Matrix has numerous enzymes that reduce NAD+ 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 of Matrix Metalloproteinase (MMP) that attacks connective tissues Therapy targeted at possible MMP inhibitors

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Effect of ROS on a. 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 between accumulation 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 cell or protein bound to cell surface

Hb can be glycosylated in blood glucose

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Inactivation by glycosylation occurs in proteins with lysine in critical location Superoxidismutase Ribonuclease Na+, K+-ATPase Experimentally inactivated when incubated 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 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
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