*OXYGEN RADICALS and AGING Rondang R. Soegianto2009

*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 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

*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

*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

*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

*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 -

*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

*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

*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)

*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

*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

*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

*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.

*Other type of age associated modification:

Protein Glycosylation (non enzymatic)

Causes aging of long lived proteinsSuch as: Collagen Crystallin

*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

*Inactivation by glycosylation occursin proteins with lysine in critical location

SuperoxydedismutaseRibonucleaseNa+, K+-ATPase

Experimentally inactivated whenincubated in glucose

*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

*With increasing age and glucose concentration

accumulation of AGE in plasma and vessel walls

cause many diabetic complications (cataract, atherosclerosis)

*Other type of protein modification dueto oxidative stress is

formation of protein-protein Cross Links

caused mainly by disulfide bonds

*Mitochondrial Dysfunction

ROS generated during aging Chronic oxidative damage to Electron Transport System (ETS)

Resulting decrease in functional capacityof cells and tissues during aging

*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

*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.

*Reference:

OXYGEN RADICALS and the

DISEASE PROCESS

Thomas, C.E., Kalyanaraman, B. eds

Harwood academic publishers