Editing Reactive oxygen species (section)

==Damaging effects==
[[File:Free Radical Toxicity.svg|framed|right|Free radical mechanisms in tissue injury. Free radical toxicity induced by xenobiotics and the subsequent detoxification by cellular enzymes (termination).]]
Effects of ROS on cell metabolism are well documented in a variety of species.<ref name="Nachiappan" /> These include not only roles in [[apoptosis]] (programmed cell death) but also positive effects such as the induction of host defence<ref>{{Cite book |title=Trends in Innate Immunity |vauthors=Rada B, Leto TL |date=2008 |publisher=Karger |isbn=978-3-8055-8548-4 |veditors=Egesten A, Schmidt A, Herwald H |series=Contributions to Microbiology |volume=15 |location=Basel |pages=164–87 |chapter=Oxidative innate immune defenses by Nox/Duox family NADPH oxidases |doi=10.1159/000136357 |pmc=2776633 |pmid=18511861}} — Review</ref><ref>{{Cite journal |vauthors=Conner GE, Salathe M, Forteza R |date=December 2002 |title=Lactoperoxidase and hydrogen peroxide metabolism in the airway |journal=American Journal of Respiratory and Critical Care Medicine |volume=166 |issue=12 Pt 2 |pages=S57–S61 |doi=10.1164/rccm.2206018 |pmid=12471090}}</ref> [[genes]] and mobilization of [[ion transporter]]s.{{Citation needed|date=May 2009}} This implicates them in control of cellular function. In particular, [[platelets]] involved in [[wound]] repair and [[blood]] [[homeostasis]] release ROS to recruit additional platelets to sites of [[injury]]. These also provide a link to the adaptive [[immune system]] via the recruitment of [[leukocyte]]s.{{Citation needed|date=May 2009}}

Reactive oxygen species are implicated in cellular activity to a variety of inflammatory responses including [[cardiovascular disease]]. They may also be involved in [[hearing impairment]] via [[cochlea]]r damage induced by [[noise health effects|elevated sound levels]], in [[ototoxicity]] of drugs such as [[cisplatin]], and in congenital deafness in both animals and humans.{{Citation needed|date=May 2009}} ROS are also implicated in mediation of [[apoptosis]] or programmed cell death and [[ischaemic]] injury. Specific examples include [[stroke]] and [[myocardial infarction|heart attack]].{{Citation needed|date=May 2009}}

In general, the harmful effects of reactive oxygen species on the cell are the damage of DNA or RNA, oxidation of polyunsaturated fatty acids in lipids ([[lipid peroxidation]]), oxidation of amino acids in proteins, and oxidative deactivation of specific enzymes by oxidation co-factors.<ref>{{Cite book |title=Genetics: analysis and principles |vauthors=Brooker RJ |publisher=McGraw-Hill Science |year=2011 |isbn=978-0-07-352528-0 |edition=4th |name-list-style=vanc}}</ref>

===Pathogen response===
When a plant recognizes an attacking pathogen, one of the first induced reactions is to rapidly produce [[superoxide]] ({{chem|O|2|-}}) or [[hydrogen peroxide]] ({{chem|H|2|O|2}}) to strengthen the cell wall. This prevents the spread of the pathogen to other parts of the plant, essentially forming a net around the pathogen to restrict movement and reproduction.

In the mammalian host, ROS is induced as an antimicrobial defense.<ref name="Functions of ROS in Macrophages and" /> To highlight the importance of this defense, individuals with [[chronic granulomatous disease]] who have deficiencies in generating ROS, are highly susceptible to infection by a broad range of microbes including ''[[Salmonella enterica]]'', ''[[Staphylococcus aureus]]'', ''[[Serratia marcescens]]'', and ''[[Aspergillus]]'' spp.

Studies on the [[homeostasis]] of the ''[[Drosophila melanogaster]]'''s intestines have shown the production of ROS as a key component of the immune response in the gut of the fly. ROS acts both as a bactericide, damaging the bacterial DNA, RNA and proteins, as well as a signalling molecule that induces repair mechanisms of the [[epithelium]].<ref>{{Cite journal |vauthors=Buchon N, Broderick NA, Lemaitre B |date=September 2013 |title=Gut homeostasis in a microbial world: insights from Drosophila melanogaster |url=http://infoscience.epfl.ch/record/189299 |journal=Nature Reviews. Microbiology |volume=11 |issue=9 |pages=615–626 |doi=10.1038/nrmicro3074 |pmid=23893105 |s2cid=8129204}}</ref> The [[uracil]] released by microorganism triggers the production and activity of DUOX, the ROS-producing enzyme in the intestine. DUOX activity is induced according to the level of uracil in the gut; under basal conditions, it is down-regulated by the protein kinase [[Mitogen-activated protein kinase|MkP3]]. The tight regulation of DUOX avoids excessive production of ROS and facilitates differentiation between benign and damage-inducing microorganisms in the gut.<ref>{{Cite journal |display-authors=6 |vauthors=Lee KA, Kim SH, Kim EK, Ha EM, You H, Kim B, Kim MJ, Kwon Y, Ryu JH, Lee WJ |date=May 2013 |title=Bacterial-derived uracil as a modulator of mucosal immunity and gut-microbe homeostasis in Drosophila |journal=Cell |volume=153 |issue=4 |pages=797–811 |doi=10.1016/j.cell.2013.04.009 |pmid=23663779 |doi-access=free}}</ref>

The manner in which ROS defends the host from invading microbe is not fully understood. One of the more likely modes of defense is damage to microbial DNA. Studies using ''Salmonella'' demonstrated that DNA repair mechanisms were required to resist killing by ROS. A role for ROS in antiviral defense mechanisms has been demonstrated via Rig-like helicase-1 and mitochondrial antiviral signaling protein. Increased levels of ROS potentiate signaling through this mitochondria-associated antiviral receptor to activate interferon regulatory factor (IRF)-3, IRF-7, and nuclear factor kappa B (NF-κB), resulting in an antiviral state.<ref name="pmid21597473">{{Cite journal |vauthors=West AP, Shadel GS, Ghosh S |date=June 2011 |title=Mitochondria in innate immune responses |journal=Nature Reviews. Immunology |volume=11 |issue=6 |pages=389–402 |doi=10.1038/nri2975 |pmc=4281487 |pmid=21597473}}</ref> Respiratory epithelial cells induce mitochondrial ROS in response to influenza infection. This induction of ROS led to the induction of type III interferon and the induction of an antiviral state, limiting viral replication.<ref name="pmid23786562">{{Cite journal |display-authors=6 |vauthors=Kim HJ, Kim CH, Ryu JH, Kim MJ, Park CY, Lee JM, Holtzman MJ, Yoon JH |date=November 2013 |title=Reactive oxygen species induce antiviral innate immune response through IFN-λ regulation in human nasal epithelial cells |journal=American Journal of Respiratory Cell and Molecular Biology |volume=49 |issue=5 |pages=855–865 |doi=10.1165/rcmb.2013-0003OC |pmc=5455605 |pmid=23786562}}</ref> In host defense against mycobacteria, ROS play a role, although direct killing is likely not the key mechanism; rather, ROS likely affect ROS-dependent signalling controls, such as cytokine production, autophagy, and granuloma formation.<ref>{{Cite journal |display-authors=6 |vauthors=Herb M, Gluschko A, Wiegmann K, Farid A, Wolf A, Utermöhlen O, Krut O, Krönke M, Schramm M |date=February 2019 |title=Mitochondrial reactive oxygen species enable proinflammatory signaling through disulfide linkage of NEMO |journal=Science Signaling |volume=12 |issue=568 |pages=eaar5926 |doi=10.1126/scisignal.aar5926 |pmid=30755476 |doi-access=free}}</ref><ref>{{Cite journal |vauthors=Deffert C, Cachat J, Krause KH |date=August 2014 |title=Phagocyte NADPH oxidase, chronic granulomatous disease and mycobacterial infections |journal=Cellular Microbiology |volume=16 |issue=8 |pages=1168–1178 |doi=10.1111/cmi.12322 |pmid=24916152 |s2cid=3489742 |doi-access=free}}</ref>

Reactive oxygen species are also implicated in activation, [[Clonal anergy|anergy]] and apoptosis of [[T cells]].<ref>{{Cite journal |vauthors=Belikov AV, Schraven B, Simeoni L |date=October 2015 |title=T cells and reactive oxygen species |journal=Journal of Biomedical Science |volume=22 |pages=85 |doi=10.1186/s12929-015-0194-3 |pmc=4608155 |pmid=26471060 |doi-access=free}}</ref>

===Oxidative damage===
In [[aerobic organism]]s the energy needed to fuel biological functions is produced in the [[mitochondria]] via the [[electron transport chain]]. Reactive oxygen species (ROS) with the potential to cause [[cell (biology)|cellular]] damage are produced along with the release of energy. ROS can damage lipids, [[DNA]], [[RNA]], and proteins, which, in theory, contributes to the [[physiology]] of [[aging]].

ROS are produced as a normal product of [[cellular metabolism]]. In particular, one major contributor to oxidative damage is [[hydrogen peroxide]] (H<sub>2</sub>O<sub>2</sub>), which is converted from [[superoxide]] that leaks from the mitochondria. [[Catalase]] and [[superoxide dismutase]] ameliorate the damaging effects of hydrogen peroxide and superoxide, respectively, by converting these compounds into [[oxygen]] and [[hydrogen peroxide]] (which is later converted to water), resulting in the production of [[benign]] [[molecule]]s. 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.<ref name="isbn0-8247-1723-6">{{Cite book |title=Understanding the process of aging: the roles of mitochondria, free radicals, and antioxidants |vauthors=Patel RP, T Cornwell T, Darley-Usmar VM |publisher=Marcel Dekker |year=1999 |isbn=0-8247-1723-6 |veditors=Packer L, Cadenas E |location=New York, NY |pages=39–56 |chapter=The biochemistry of nitric oxide and peroxynitrite: implications for mitochondrial function}}</ref>

===Impairment of cognitive function===
Memory capabilities decline with age, evident in human degenerative diseases such as [[Alzheimer's disease]], which is accompanied by an accumulation of oxidative damage. Current studies demonstrate that the accumulation of ROS can decrease an organism's [[physical fitness|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 in which old rats were given mitochondrial [[metabolite]]s and then given [[cognitive tests]]. Results showed that the [[rat]]s performed better after receiving the metabolites, suggesting that the metabolites reduced oxidative damage and improved mitochondrial function.<ref name="pmid11854529">{{Cite journal |display-authors=6 |vauthors=Liu J, Head E, Gharib AM, Yuan W, Ingersoll RT, Hagen TM, Cotman CW, Ames BN |date=February 2002 |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=Proceedings of the National Academy of Sciences of the United States of America |volume=99 |issue=4 |pages=2356–2361 |bibcode=2002PNAS...99.2356L |doi=10.1073/pnas.261709299 |pmc=122369 |pmid=11854529 |doi-access=free}}</ref> Accumulating oxidative damage can then affect the efficiency of mitochondria and further increase the rate of ROS production.<ref name="pmid1355616">{{Cite journal |vauthors=Stadtman ER |date=August 1992 |title=Protein oxidation and aging |url=https://zenodo.org/record/1230934 |journal=Science |volume=257 |issue=5074 |pages=1220–1224 |bibcode=1992Sci...257.1220S |doi=10.1126/science.1355616 |pmid=1355616}}</ref> The accumulation of oxidative damage and its implications for aging depends on the particular [[tissue (biology)|tissue]] type where the damage is occurring. Additional experimental results suggest that oxidative damage is responsible for age-related decline in [[brain]] functioning. Older [[gerbil]]s were found to have higher levels of oxidized protein in comparison to younger gerbils. Treatment of old and young [[mice]] with a [[spin trapping]] compound caused a decrease in the level of oxidized proteins in older gerbils but did not have an effect on younger gerbils. In addition, older gerbils performed cognitive tasks better during treatment but ceased functional capacity when treatment was discontinued, causing oxidized protein levels to increase. This led researchers to conclude that oxidation of cellular proteins is potentially important for brain function.<ref name="CarneyStarke-Reed1991">{{Cite journal |vauthors=Carney JM, Starke-Reed PE, Oliver CN, Landum RW, Cheng MS, Wu JF, Floyd RA |date=May 1991 |title=Reversal of age-related increase in brain protein oxidation, decrease in enzyme activity, and loss in temporal and spatial memory by chronic administration of the spin-trapping compound N-tert-butyl-alpha-phenylnitrone |journal=Proceedings of the National Academy of Sciences of the United States of America |volume=88 |issue=9 |pages=3633–3636 |bibcode=1991PNAS...88.3633C |doi=10.1073/pnas.88.9.3633 |pmc=51506 |pmid=1673789 |doi-access=free}}</ref>