- Reactive oxygen species
Reactive oxygen species (ROS) are ions or very small molecules that include
oxygen ions, free radicals, and peroxides, both inorganic and organic. They are highly reactive due to the presence of unpaired valence shell electrons.ROS form as a natural byproduct of the normal metabolism of oxygenand have important roles in cell signaling. However, during times of environmental stress ROS levels can increase dramatically, which can result in significant damage to cell structures. This cumulates into a situation known as oxidative stress. They are also generated by exogenous sources such as ionizing radiation.
Cells are normally able to defend themselves against ROS damage through the use of
enzymessuch as superoxide dismutases and catalases. Small molecule antioxidants such as ascorbic acid(vitamin C), tocopherol(vitamin E), uric acid, and glutathionealso play important roles as cellular antioxidants. Similarly, polyphenol antioxidantsassist in preventing ROS damage by scavenging free radicals. In contrast, the antioxidant ability of the extracellular space is relatively less--e.g., the most important plasma antioxidant in humans is probably uric acid.
Effects of ROS on cell metabolism have been well documented in a variety of species. These include not only roles in
apoptosis(programmed cell death), but also positive effects such as the induction of host defence genesand mobilisation of ion transport systems. This is implicating them more frequently with roles in redox signalingor oxidative signaling. In particular, plateletsinvolved in woundrepair and blood homeostasisrelease ROS to recruit additional platelets to sites of injury. These also provide a link to the adaptive immune systemvia the recruitment of leukocytes.
Reactive oxygen species are implicated in cellular activity to a variety of inflammatory responses including
cardiovascular disease. They may also be involved in hearing impairmentvia cochlear damage induced by elevated sound levels, ototoxicity of drugs such as cisplatin, and in congenital deafness in both animals and humans. Redox signalingis also implicated in mediation of apoptosisor programmed cell death and ischaemicinjury. Specific examples include strokeand heart attack.
Generally, harmful effects of reactive oxygen species on the cell are most often:
# damage of DNA
# oxidations of polydesaturated fatty acids in lipids
# oxidations of amino acids in proteins
# Oxidatively inactivate specific enzymes by oxidation of co-factors
aerobic organisms the energy needed to fuel biological functions is produced in the mitochondriavia the electron transport chain. In addition to energy, reactive oxygen species (ROS) are produced which have the potential to cause cellular damage. ROS can damage DNA, RNA, and proteins which theoretically contributes to the physiologyof ageing.
ROS are produced as a normal product of
cellular metabolism. In particular, one major contributor to oxidative damage is hydrogen peroxide(H2O2) which is converted from superoxidethat leaks from the mitochondria. Within the cell there is catalaseand superoxide dismutasethat help to minimize the damaging effects of hydrogen peroxide by converting it into oxygenand water, benign molecules, however this conversion is not 100% efficient, and residual peroxides persist in the cell. While ROS are produced as a product of normal cellular functioning, excessive amounts can cause deleterious effects. [Patel RP, T Cornwell, and VM Darley-USMAR: The biochemistry of nitric oxide and peroxynitrite: implications for mitochondrial function. In: Understanding the process of ageing: The roles of mitochondria, free radicals, and antioxidants. ( 1999) Eds: E Cadenas and L Packer, Marcel Dekker, Inc. NY. Basel 39-40]
Memory capabilities decline with age, evident in human degenerative diseases such as
Alzheimer’s diseasewhich is accompanied by an accumulation of oxidative damage. Current studies demonstrate that the accumulation of ROS can decrease an organism’s fitness because oxidative damage is a contributor to senescence. In particular, the accumulation of oxidative damage may lead to cognitive dysfunction as demonstrated in a study where old rats were given mitochondrial metabolites and then given cognitive tests, results showed that the rats performed better after receiving the metabolites, suggesting that the metabolites reduced oxidative damage and improved mitochondrial function. [cite journal |author=Liu J, Head E, Gharib AM, "et al" |title=Memory loss in old rats is associated with brain mitochondrial decay and RNA/DNA oxidation: partial reversal by feeding acetyl-L-carnitine and/or R-alpha -lipoic acid |journal=Proc. Natl. Acad. Sci. U.S.A. |volume=99 |issue=4 |pages=2356–61 |year=2002 |month=February |pmid=11854529 |doi=10.1073/pnas.261709299 |url=http://www.pnas.org/cgi/pmidlookup?view=long&pmid=11854529 |accessdate=2008-05-19] Accumulating oxidative damage can then affect the efficiency of mitochondria and further increase the rate of ROS production. [cite journal |author=Stadtman ER |title=Protein oxidation and aging |journal=Science (journal) |volume=257 |issue=5074 |pages=1220–4 |year=1992 |month=August |pmid=1355616 |url=http://www.sciencemag.org/cgi/pmidlookup?view=long&pmid=1355616 |accessdate=2008-05-19 |doi=10.1126/science.1355616]
The accumulation of oxidative damage and its implications for aging depends on the particular tissue type where the damage is occurring. Additional experimental results suggest that oxidative damage is responsible for age related decline in
brainfunctioning. Older gerbilswere found to have higher levels of oxidized protein in comparison to younger gerbils. When old and young micewere treated with a spin trapping compound the level of oxidized proteins decreased in older gerbils but did not have an effect on younger gerbils. Additionally, older gerbils performed cognitive tasks better during treatment but ceased functional capacity when treatment was discontinued causing oxidized protein levels to increase. This lead researchers to conclude that oxidation of cellular proteins is potentially important for brain function (Carney, 1991).
Free radicals are also produced inside (and also released towards the cytosol [Muller, F. (
2000) The Nature and Mechanism of Superoxide production by the Electron Transport Chain: Its relevance to aging. J. Amer. Aging Assoc. 23, 227-253] cite journal |author=Han D, Williams E, Cadenas E |title=Mitochondrial respiratory chain-dependent generation of superoxide anion and its release into the intermembrane space |journal=Biochem. J. |volume=353 |issue=Pt 2 |pages=411–6 |year=2001 |month=January |pmid=11139407 |url=http://www.biochemj.org/bj/353/0411/bj3530411.htm |accessdate=2008-05-19 |doi=10.1042/0264-6021:3530411] ) organelles, such as the mitochondrion. Mitochondria convert energy for the cell into a usable form, adenosine triphosphate(ATP). The process in which ATP is produced, called oxidative phosphorylation, involves the transport of protons (hydrogen ions) across the inner mitochondrial membrane by means of the electron transport chain. In the electron transport chain, electrons are passed through a series of proteins via oxidation-reduction reactions, with each acceptor protein along the chain having a greater reduction potential than the last. The last destination for an electron along this chain is an oxygen molecule. Normally the oxygen is reduced to produce water; however, in about 0.1-2% of electrons passing through the chain(this number derives from studies in isolated mitochondria, though the exact rate in live organisms is yet to be fully agreed upon), oxygen is instead prematurely and incompletely reduced to give the superoxide radical,·O2-, most well documented for Complex Iand Complex III. Superoxide is not particularly reactive in and of itself, but can inactivate specific enzymes or initiate lipid peroxidation in its HO2· form. If too much damage is caused to its mitochondria, a cell undergoes apoptosisor programmed cell death.
Bcl-2 proteins are layered on the surface of the mitochondria, detect damage, and activate a class of proteins called Bax, which punch holes in the mitochondrial membrane, causing cytochrome C to leak out. This cytochrome C binds to Apaf-1, or apoptotic protease activating factor-1, which is free-floating in the cell’s cytoplasm. Using energy from the ATPs in the mitochondrion, the Apaf-1 and cytochrome C bind together to form apoptosomes. The apoptosomes binds to and activates caspase-9, another free-floating protein. The caspase-9 then cleaves the proteins of the mitochondrial membrane, causing it to break down and start a chain reaction of protein denaturation and eventually phagocytosis of the cell.
Cause of aging
According to the
Free-radical theory, oxidative damage intiated by reactive oxygen species is a major contributor to the functional decline that is characteristic of aging. While studies in invertebrate models indicate that animals genetically engineered to lack specific antioxidant enzymes (such as SOD) generally show a shortened lifespan (as one would expect from the theory), the converse, increasing the levels of antioxidant enzymes, has yielded inconsistent effects on lifespan (though some well-performed studies in Drosophilado show that lifespan can be increased by the overexpression of MnSOD or glutathione biosynthesizing enzymes). In mice, the story is somewhat similar. Deleting antioxidant enzymes generally yields shorter lifespan, though overexpression studies have not (with some recent exceptions), consistently extended lifespan [1 Muller, F. L., Lustgarten, M. S., Jang, Y., Richardson, A. and Van Remmen, H. (2007) Trends in oxidative aging theories. Free Radic. Biol. Med. 43, 477-503] .
Superoxide dismutase(SOD) is present in two places naturally in the cell. SOD that is present in the mitochondria contains manganese (MnSod). This SOD is transcribed in the nucleus and has a mitochondrial targeting sequence, thereby localizing it to the mitochondrial matrix. SOD that is present in the cytoplasm of the cell contains copper and zinc (CuZnSod). The genes that control the formation of SOD are located on chromosomes 21, 6, and 4. When superoxide dismutase comes in contact with superoxide, it reacts with it and forms hydrogen peroxide. The stoichiometry of this reaction is that for each 2 superoxide radicals encountered by SOD, 1 H2O2 is formed. This hydrogen peroxide is dangerous in the cell because it can easily transform into a hydroxyl radical(via reaction with Fe2+: Fenton chemistry), one of the most destructive free radicals. Catalase, which is concentrated in peroxisomes located next to mitochondria but formed in the rough endoplasmic reticulum and located everywhere in the cell, reacts with the hydrogen peroxide and forms water and oxygen. Glutathione peroxidase reduces hydrogen peroxide by transferring the energy of the reactive peroxides to a very small sulfur containing protein called glutathione. The selenium contained in these enzymes acts as the reactive center, carrying reactive electrons from the peroxide to the glutathione. Peroxiredoxins also degrade H2O2, both within the mitochondria, cytosol and nucleus.
Reactive carbon species
Evolution of dietary antioxidants
* Sen, C.K. (2003) The general case for redox control of wound repair, "Wound Repair and Regeneration", 11, 431-438
* Krötz, F., Sohn, HY., Gloe, T., Zahler, S., Riexinger, T., Schiele, T.M., Becker, B.F., Theisen, K., Klauss, V., Pohl, U. (2002) NAD(P)H oxidase-dependent platelet superoxide anion release increases platelet recruitment, "Blood", 100, 917-924
* Pignatelli, P. Pulcinelli, F.M., Lenti, L., Gazzaniga, P.P., Violi, F. (1998) Hydrogen Peroxide Is Involved in Collagen-Induced Platelet Activation, "Blood", 91 (2), 484-490
* Guzik, T.J., Korbut, R., Adamek-Guzik, T. (2003) Nitric oxide and superoxide in inflammation and immune regulation, "Journal of Physiology and Pharmacology", 54 (4), 469-487
* [http://www.drproctor.com/crcpap2.htm Free Radicals and Human Disease, a Review]
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