oxidative stress

Definition: Oxydative stress is the accumulation of oxygen-free radicals or reactive oxygen species (ROS).

Cells generate energy by reducing molecular oxygen to water. During this process, small amounts of partially reduced reactive oxygen forms are produced as an unavoidable byproduct of mitochondrial respiration.

Pathogeny

Some of these forms are free radicals that can damage lipids, proteins, and nucleic acids. They are referred to as reactive oxygen species (ROS).

Cells have defense systems to prevent injury caused by these products. An imbalance between free radical-generating and radical-scavenging systems results in oxidative stress, a condition that has been associated with the cell injury seen in many pathologic conditions.

Free radical-mediated damage contributes to such varied processes:

 chemical injury
 radiation injury
 ischemia-reperfusion injury (induced by restoration of blood flow in ischemic tissue)
 cellular aging
 microbial killing by phagocytes

The effects of reactive oxygen species (ROS) are wide-ranging, but three reactions are particularly relevant to cell injury:

 membrane lipid peroxidation

Free radicals in the presence of oxygen may cause peroxidation of lipids within plasma and organellar membranes.

Oxidative damage is initiated when the double bonds in unsaturated fatty acids of membrane lipids are attacked by oxygen-derived free radicals, particularly by OH.

The lipid-free radical interactions yield peroxides, which are themselves unstable and reactive, and an autocatalytic chain reaction ensues (called propagation), which can result in extensive membrane, organellar, and cellular damage.

Other more favorable termination options take place when the free radical is captured by a scavenger, such as vitamin E, embedded in the cell membrane.

 protein oxidative modification of proteins

Free radicals promote oxidation of amino acid residue side chains, formation of protein-protein cross-linkages (e.g., disulfide bonds), and oxidation of the protein backbone, resulting in protein fragmentation.

Oxidative modification enhances degradation of critical proteins by the multicatalytic proteasome complex.

 DNA lesions

Reactions with thymine in nuclear and mitochondrial DNA produce single-stranded breaks in DNA. This DNA damage has been implicated in cell aging and in malignant transformation of cells.

Free radicals removing

Cells have developed multiple mechanisms to and thereby minimize injury. Free radicals are inherently unstable and generally decay spontaneously.

Superoxide, for example, is unstable and decays (dismutates) spontaneously into oxygen and hydrogen peroxide in the presence of water. There are, however, several nonenzymatic and enzymatic systems that contribute to inactivation of free radical reactions:

 antioxidants either block the initiation of free radical formation or inactivate (e.g., scavenge) free radicals and terminate radical damage. Examples are the lipid-soluble vitamins E and A as well as ascorbic acid and glutathione in the cytosol.

  iron and copper can catalyze the formation of reactive oxygen species. The levels of these reactive forms are minimized by binding of the ions to storage and transport proteins (e.g., transferrin, ferritin, lactoferrin, and ceruloplasmin), thereby minimizing OH formation.

 A series of enzymes acts as free radical-scavenging systems and break down hydrogen peroxide and superoxide anion. These enzymes are located near the sites of generation of these oxidants:

• catalase, present in peroxisomes, which decomposes H2O2 (2 H2O2 → O2 + 2 H2O).

• superoxide dismutases (SODs) are found in many cell types and convert superoxide to H2O2 (2 O2- + 2 H → H2O2 + O2).23
  • copper-zinc-superoxide dismutases SOD1 and SOD3 , which are found in the cytosol
  • manganese-superoxide dismutase SOD2, which is localized in mitochondria

• glutathione peroxidase also protects against injury by catalyzing free radical breakdown (H2O2 + 2 GSH → GSSG [glutathione homodimer] + 2 H2O, or 2 OH + 2 GSH → GSSG + 2 H2O).
  • The intracellular ratio of oxidized glutathione (GSSG) to reduced glutathione (GSH) is a reflection of the oxidative state of the cell and is an important aspect of the cell’s ability to detoxify reactive oxygen species.

Reactive oxygen species from endogenous and environmental sources induce oxidative damage to DNA, and hence pose an enormous threat to the genetic integrity of cells.

This oxidative DNA damage is restored by the base excision repair (BER) pathway that is conserved from bacteria to humans and is initiated by DNA glycosylases, which simply remove the aberrant base from the DNA backbone by hydrolyzing the N-glycosidic bond (monofunctional DNA glycosylase), or further catalyze the incision of a resulting abasic site (bifunctional DNA glycosylase).

In human cells, oxidative pyrimidine lesions are generally removed by hNTH1, hNEIL1, or hNEIL2, whereas oxidative purine lesions are removed by hOGG1. hSMUG1 excises a subset of oxidative base damage that is poorly recognized by the above enzymes.

Unlike these enzymes, hMYH removes intact A misincorporated opposite template 8-oxoguanine during DNA replication.

Although hNTH1, hOGG1, and hMYH account for major cellular glycosylase activity for inherent substrate lesions, mouse models deficient in the enzymes exhibit no overt phenotypes such as the development of cancer, implying backup mechanisms.

Contrary to the mouse model, hMYH mutations have been shown to lead to a multiple colorectal adenoma syndrome and high colorectal cancer risk.

For cleavage of the N-glycosidic bond, bifunctional DNA glycosylases (hNTH1, hNEIL1, hNEIL2, and hOGG1) use Lys or Pro for direct attack on sugar C1’, whereas monofunctional DNA glycosylases (hSMUG1 and hMYH) use an activated water molecule.

DNA glycosylases for oxidative damage, if not all, are covalently trapped by DNA containing 2-deoxyribonolactone or oxanine. Thus, the depletion of functional DNA glycosylases using covalent trapping may reduce the BER capacity of cancer cells, hence potentiating the efficacy of anticancer drugs or radiation therapy.

Localization

 oxidative stress in the central nervous system (17168738)

See also

 oxidative stress markers

References

 Lehtinen MK, Bonni A. Modeling oxidative stress in the central nervous system. Curr Mol Med. 2006 Dec;6(8):871-81. PMID: 17168738

 Kaneto H, Matsuoka TA, Katakami N, Kawamori D, Miyatsuka T, Yoshiuchi K, Yasuda T, Sakamoto K, Yamasaki Y, Matsuhisa M. Oxidative stress and the JNK pathway are involved in the development of type 1 and type 2 diabetes. Curr Mol Med. 2007 Nov;7(7):674-86. PMID: 18045145

 Salvemini D, Cuzzocrea S: Superoxide, superoxide dismutase and ischemic injury. Curr Opin Investig Drugs 3:886, 2002.

 Barzilai A, Yamamoto K. DNA damage responses to oxidative stress. DNA Repair (Amst). 2004 Aug-Sep;3(8-9):1109-15. PMID: 15279799

 Ide H, Kotera M. Human DNA glycosylases involved in the repair of oxidatively damaged DNA. Biol Pharm Bull. 2004 Apr;27(4):480-5. PMID: 15056851

 Andersen JK. Oxidative stress in neurodegeneration: cause or consequence? Nat Med. 2004 Jul;10 Suppl:S18-25. PMID: 15298006

 Purdom S, Chen QM. p66(Shc): at the crossroad of oxidative stress and the genetics of aging. Trends Mol Med. 2003 May;9(5):206-10. PMID: 12763525

 MacNee W, Rahman I. Is oxidative stress central to the pathogenesis of chronic obstructive pulmonary disease? Trends Mol Med. 2001 Feb;7(2):55-62. PMID: 11286755

 Finkel T, Holbrook NJ: Oxidants, oxidative stress, and the biology of ageing. Nature 408:239, 2000.