Professional Documents
Culture Documents
Reactive Oxygen Species & Signal Trans Duct Ion 2
Reactive Oxygen Species & Signal Trans Duct Ion 2
unpaired electrons. There are many types of radicals, but the most prominent in biological systems are derived from oxygen collectively known as Reactive Oxygen Species (ROS),
occur in the body; some as necessary intermediates of enzymatic reactions. Most are produced in the ETC when oxygen is reduced to water in the mitochondria. O2 reduction H2 O During this conversion various reactive oxygen species are formed! .O .OHO2 H2O2 H2O 2
(oxygen) (superoxide) (hydrogen peroxide) (hydroxyl ion) (water)
Overproduction of ROS
Neutrophils are specialized in ROS formation which
destroy pathogens as part of host defence. When cells are exposed to abnormal environments such as hypoxia and hyperoxia. From ionizing radiation in biological systems. Ionizing radiation will ionize molecular oxygen by pushing an electron in its outer orbit. If oxygen species are overproduced it will be difficult for the cell to detoxify them and repair the damages they make! Result: Oxidative stress! So Oxidative stress is an imbalance btw reactive oxygen species and antioxidants!
lipids, proteins and DNA caused by ROS implicate them in many disease processes, ranging from arthritis, atherosclerosis, pulmonary fibrosis, cancer, neurodegenerative diseases, and aging Toxic effects such as damage to cell membranes initiated by lipid peroxidation. A common target for peroxidation is unsaturated fatty acids present in membrane phospholipids
Lipid peroxidation....
increased membrane rigidity decreased activity of membrane-bound enzymes (e.g. sodium pumps) altered activity of membrane receptors. altered permiability
Intracellular antioxidants:
Intracellular antioxidants
Vitamin E; a lipid soluble antioxidant that traps
peroxy radicals while doing so it itself becomes a radical Vitamin C regenerates back vitamin E from its radical form
Enzymatic antioxidants
Superoxide dismutases (SODs)
Mostly found in the mitochondria They depend on cofactors such as manganese, copper or zinc
for their antioxidant activity. They convert 2 superoxide ions into oxygen and hydrogen peroxide
oxygen!
Site of location; peroxisomes
SIGNAL
TRANSDUCTION
Extracellular Signal
(growth factor/cytokines/neurotransmitter/hormone)
Binds to specific Receptor
of transcription factors
activation/inactivation of gene transcription that
Receptor + hormone (upstream signaling) Receptor-ligand complex Intracellular ROS production (downstream signaling) activates Other pathways promote regions of intermediate response genes governing cell proliferation, differentiation, etc. ROS are involved in both upregulation and downregulation pathways!
metabolism but also essential participants in cell signaling and regulation The cellular functions/toxic properties of ROS is dependent on their concentration. For e.g. when produced in low concentrations by nitric oxide synthase(NOS) NO functions as a signaling molecule mediating vasodilation While when produced in high concentrations in macrophages, it is a toxic oxidant for microbicidal killing
enzymatic and nonenzymatic sources any electron-transferring protein or enzymatic system can result in the formation of ROS as byproducts ROS are mostly produced in the mitochondria, H2O2 can diffuse out in the cytoplasm while O2.remains trapped in. O2 -generating microsomal NADH oxidoreductase may function as a potential pulmonary artery O2 sensor in pulmonary artery smooth muscle cells
Electron leaks from these enzymatic systems gives rise to ROS that can damage cellular DNA Peroxisomes are an important source of total cellular H2O2 production. They contain a number of H2O2-generating enzymes including glycolate oxidase, d-amino acid oxidase. Peroxisomal catalase utilizes H2O2 produced by these oxidases to oxidize a variety of other substrates in peroxidative reactions e.g. detoxification of alcohol in the liver Intracellular soluble enzymes such as xanthine oxidase, aldehyde oxidase, can generate ROS during catalytic cycling
epinephrine can be an important source of intracellular ROS production. Prooxidant effects of dopamine autooxidation is implicated in the pathogenesis of neurodegenerative diseases such as Parkinson's disease Plasma membrane-associated oxidases have been implicated as the sources of most growth factor- and/or cytokine-stimulated oxidant production The phagocytic NADPH oxidase, which serves a specialized function in host defense against invading microorganisms
present in nonphagocytic cells. P22phox is a component of NADPH oxidase and plays a key role in its activation Expression of p22phox has been demonstrated in the adventitial smooth muscle cells of coronary arteries and the aorta Increased aortic adventitial O2 production contributes to hypertension by blocking the vasodilatory effects of NO ROS production in coronary arteries is related to hypertension
signaling :Cytokine receptors Receptor tyrosine kinases (RTKs) Receptor serine/threonine kinases G-protein coupled receptor These receptors will generate intracellular signals for ROS production
the expression of cell adhesion molecules from genes production of chemokines In pathophysiological conditions such as induction of cardiac myocyte
hypertrophy
2.IFN- (activator of the phagocytic NADPH oxidase) Stimulates cyclooygenase-dependent peroxide production in human hepatocyte Resistance to bacteria
These growth factors that act on receptor tyrosine kinases (RTKs) include : PDGF (plasma dependent growth factor) EGF (epidermal growth factor) FGF (fibroblast growth factor)
PDGF
Increases intracellular concentrations of hydrogen peroxides Induce tyrosine phosphorylation MAPK activation DNA synthesis & chemotaxis Regulates gene expression by .O2 dependent pathways
.O 2
produced
involved in the upregulation of inducible NOS & NO dependent release of PGE2 in fibroblasts
induces fever
TGF- Stimulates extracellular production of ROS Regulates a number of physiological actions Apoptosis, collagen synthesis, growth inhibitory effects
G protein-coupled receptors
The ligands for these receptors include: ANG II (Angiotensin II) Serotonin (5-hydroxytryptamine) Bradykinin Thrombin
Angiotensin II activates both NADH- and NADPH-dependent O2 production in vascular smooth muscle cells A variety of physiological actions of ANG II are mediated by ROS its vasopressor activity, smooth muscle cell hypertrophy, activation of cell survival PK Akt/PKB, induction of insulin-like growth factor-1 receptor
conditions This is accomplished by the redox-buffering capacity of intracellular thiols, primarily glutathione (GSH)and thioredoxin (TRX). They reduce both H2O2 and lipid peroxides, reactions that are catalyzed by peroxidases e.g. GSH peroxidase catalyzes the reaction H2O2 + 2GSH 2H2O + GSSG GSH and TRX are antioxidants that play important roles in cell signaling
Conclusion
ROS are mediators of cell signaling They cause a series of changes during cell signaling
References
http://www.jleukbio.org/content/65/3/337.full.pdf http://www.sciencedirect.com/science/article/pii/S