{{short description|Reactive oxygen species produced by mitochondria}} thumb|Production of mitochondrial ROS, mitochondrial ROS '''Mitochondrial ROS''' ('''mtROS''' or '''mROS''') are reactive oxygen species (ROS) that are produced by mitochondria.<ref name="pmid23442817">{{cite journal |vauthors=Li X, Fang P, Mai J, etal |title = Targeting mitochondrial reactive oxygen species as novel therapy for inflammatory diseases and cancers | journal = J Hematol Oncol | volume = 6 | issue = 19 |page = 19 |date=February 2013 | pmid = 23442817|doi = 10.1186/1756-8722-6-19 | pmc=3599349 |doi-access = free }}</ref><ref>{{cite journal |last1=Reichart |first1=Gesine |title=Mitochondrial complex IV mutation increases ROS production and reduces lifespan in aged mice. |journal=Acta Physiologica |article-number=e13214 |date=October 30, 2018 |doi=10.1111/apha.13214|pmid=30376218 |volume=225|issue=4 |s2cid=53115753 }}</ref><ref name="pmid27925481">{{cite journal |vauthors=Li X, Fang P, etal |title = Mitochondrial ROS, uncoupled from ATP synthesis, determine endothelial activation for both physiological recruitment of patrolling cells and pathological recruitment of inflammatory cells. | journal = Can J Physiol Pharmacol | volume = 95 | issue = 3 |pages = 247–252 |date=March 2017 | pmid = 27925481|doi = 10.1139/cjpp-2016-0515 | pmc=5336492}}</ref> Generation of mitochondrial ROS mainly takes place at the electron transport chain located on the inner mitochondrial membrane during the process of oxidative phosphorylation. Leakage of electrons at complex I and complex III from electron transport chains leads to partial reduction of oxygen to form superoxide. Subsequently, superoxide is quickly dismutated to hydrogen peroxide by two dismutases including superoxide dismutase 2 (SOD2) in mitochondrial matrix and superoxide dismutase 1 (SOD1) in mitochondrial intermembrane space. Collectively, both superoxide and hydrogen peroxide generated in this process are considered as mitochondrial ROS.<ref name="pmid23442817" />
Once thought as merely the by-products of cellular metabolism, mitochondrial ROS are increasingly viewed as important signaling molecules,<ref>{{Cite journal|last1=Trewin|first1=Adam J|last2=Bahr|first2=Laura L|last3=Almast|first3=Anmol|last4=Berry|first4=Brandon J|last5=Wei|first5=Alicia Y|last6=Foster|first6=Thomas H|last7=Wojtovich|first7=Andrew P|date=2019-03-19|title=Mitochondrial ROS generated at the complex-II matrix or intermembrane space microdomain have distinct effects on redox signaling and stress sensitivity in C. elegans.|journal=Antioxidants & Redox Signaling|volume=31|issue=9|pages=594–607|doi=10.1089/ars.2018.7681|pmid=30887829|issn=1523-0864|pmc=6657295}}</ref> whose levels of generation at 11 currently-identified sites vary depending on cellular energy supply and demand.<ref>{{Cite journal|last1=Trewin|first1=Adam J.|last2=Parker|first2=Lewan|last3=Shaw|first3=Christopher S.|last4=Hiam|first4=Danielle S.|last5=Garnham|first5=Andrew|last6=Levinger|first6=Itamar|last7=McConell|first7=Glenn K.|last8=Stepto|first8=Nigel K.|date=November 2018|title=Acute HIIE elicits similar changes in human skeletal muscle mitochondrial H 2 O 2 release, respiration, and cell signaling as endurance exercise even with less work|journal=American Journal of Physiology. Regulatory, Integrative and Comparative Physiology|volume=315|issue=5|pages=R1003–R1016|doi=10.1152/ajpregu.00096.2018|pmid=30183338|issn=0363-6119|doi-access=free|hdl=10536/DRO/DU:30113706|hdl-access=free}}</ref><ref>{{Cite journal|last1=Goncalves|first1=Renata L. S.|last2=Quinlan|first2=Casey L.|last3=Perevoshchikova|first3=Irina V.|last4=Hey-Mogensen|first4=Martin|last5=Brand|first5=Martin D.|date=2015-01-02|title=Sites of Superoxide and Hydrogen Peroxide Production by Muscle Mitochondria Assessed ex Vivo under Conditions Mimicking Rest and Exercise|journal=Journal of Biological Chemistry|volume=290|issue=1|pages=209–227|doi=10.1074/jbc.M114.619072|issn=0021-9258|pmc=4281723|pmid=25389297|doi-access=free}}</ref> At low levels, mitochondrial ROS are considered to be important for metabolic adaptation as seen in hypoxia.<ref name="pmid23442817" /> Mitochondrial ROS, stimulated by danger signals such as lysophosphatidylcholine and Toll-like receptor 4 and Toll-like receptor 2 bacterial ligands lipopolysaccharide (LPS) and lipopeptides, are involved in regulating inflammatory response.<ref name="li-2016">{{cite journal |title = Mitochondrial Reactive Oxygen Species Mediate Lysophosphatidylcholine-Induced Endothelial Cell Activation | journal = Arteriosclerosis, Thrombosis, and Vascular Biology |date=April 2016 | pmid = 27127201 |doi = 10.1161/ATVBAHA.115.306964 |volume=36 | issue = 6 |pmc=4882253 |pages=1090–100 |vauthors=Li X, Fang P, Li Y, Kuo YM, Andrews AJ, Nanayakkara G, Johnson C, Fu H, Shan H, Du F, Hoffman NE, Yu D, Eguchi S, Madesh M, Koch WJ, Sun J, Jiang X, Wang H, Yang X}}</ref><ref name="pmid21525932">{{cite journal |vauthors=West AP |title = TLR signalling augments macrophage bactericidal activity through mitochondrial ROS. | journal = Nature | volume = 472 | issue = 7344 |date=April 2011 | pmid = 21525932|doi = 10.1038/nature09973 | pmc=3460538 | pages=476–480|bibcode = 2011Natur.472..476W }}</ref> Finally, high levels of mitochondrial ROS activate apoptosis/autophagy pathways capable of inducing cell death.<ref name="pmid21832045">{{cite journal | author = Finkel T | title = Signal transduction by mitochondrial oxidants | journal = J Biol Chem | volume = 287 | issue = 7 |date=February 2012 | pmid = 21832045 | doi = 10.1074/jbc.R111.271999 | pages=4434–40 | pmc=3281633| doi-access = free }}</ref>
==COVID-19==
Monocytes/macrophages are the most enriched immune cell types in the lungs of COVID-19 patients and appear to have a central role in the pathogenicity of the disease. These cells adapt their metabolism upon infection and become highly glycolytic, which facilitates SARS-CoV-2 replication. The infection triggers mitochondrial ROS production, which induces stabilization of hypoxia-inducible factor-1α (HIF1A) and consequently promotes glycolysis. HIF1A-induced changes in monocyte metabolism by SARS-CoV-2 infection directly inhibit T cell response and reduce epithelial cell survival. Targeting mitochondrial ROS may have great therapeutic potential for the development of novel drugs to treat patients with coronavirus.<ref name="pmid32533110">{{cite journal | author = Cavounidis A, Mann EH | title = SARS-CoV-2 has a sweet tooth | journal = Nature Reviews Immunology |date=June 2020 | volume = 20 | issue = 8 | page = 460 | pmid = 32533110 | doi = 10.2139/ssrn.3606770 | pmc=7291939}}</ref>
==Aging==
Mitochondrial ROS can promote cellular senescence and aging phenotypes in the skin of mice.<ref name="pmid22278880">{{cite journal |vauthors=Velarde MC, Flynn JM, Day NU, Melov S, Campisi J |title=Mitochondrial oxidative stress caused by Sod2 deficiency promotes cellular senescence and aging phenotypes in the skin |journal=Aging (Albany NY) |volume=4 |issue=1 |pages=3–12 |date=January 2012 |pmid=22278880 |pmc=3292901 |doi=10.18632/aging.100423 }}</ref> Ordinarily mitochondrial SOD2 protects against mitochondrial ROS. Epidermal cells in mutant mice with a genetic SOD2 deficiency undergo cellular senescence, nuclear DNA damage, and irreversible arrest of proliferation in a portion of their keratinocytes.<ref name="pmid22278880" /><ref name="pmid26240345">{{cite journal |vauthors=Velarde MC, Demaria M, Melov S, Campisi J |title=Pleiotropic age-dependent effects of mitochondrial dysfunction on epidermal stem cells |journal=Proc. Natl. Acad. Sci. U.S.A. |volume=112 |issue=33 |pages=10407–12 |date=August 2015 |pmid=26240345 |pmc=4547253 |doi=10.1073/pnas.1505675112 |bibcode=2015PNAS..11210407V |doi-access=free }}</ref>
Mutant mice with a conditional deficiency for mitochondrial SOD2 in connective tissue have an accelerated aging phenotype.<ref name="pmid21108731">{{cite journal |vauthors=Treiber N, Maity P, Singh K, Kohn M, Keist AF, Ferchiu F, Sante L, Frese S, Bloch W, Kreppel F, Kochanek S, Sindrilaru A, Iben S, Högel J, Ohnmacht M, Claes LE, Ignatius A, Chung JH, Lee MJ, Kamenisch Y, Berneburg M, Nikolaus T, Braunstein K, Sperfeld AD, Ludolph AC, Briviba K, Wlaschek M, Florin L, Angel P, Scharffetter-Kochanek K |title=Accelerated aging phenotype in mice with conditional deficiency for mitochondrial superoxide dismutase in the connective tissue |journal=Aging Cell |volume=10 |issue=2 |pages=239–54 |date=April 2011 |pmid=21108731 |doi=10.1111/j.1474-9726.2010.00658.x |doi-access= }}</ref> This aging phenotype includes weight loss, skin atrophy, kyphosis (curvature of the spine), osteoporosis, muscle degeneration and reduced life span.
==DNA damage==
Mitochondrial ROS attack DNA readily, generating a variety of DNA damages such as oxidized bases and strand breaks. The major mechanism that cells use to repair oxidized bases such as 8-hydroxyguanine, formamidopyrimidine and 5-hydroxyuracil is base excision repair (BER).<ref name="pmid18978338">{{cite journal |vauthors=Maynard S, Schurman SH, Harboe C, de Souza-Pinto NC, Bohr VA |title=Base excision repair of oxidative DNA damage and association with cancer and aging |journal=Carcinogenesis |volume=30 |issue=1 |pages=2–10 |date=January 2009 |pmid=18978338 |pmc=2639036 |doi=10.1093/carcin/bgn250 }}</ref> BER occurs in both the cell nucleus and in mitochondria.
== References == {{Reflist}}
Category:Free radicals Category:Mitochondria Category:Oxygen