Editing Respiratory complex I (section)

==Production of superoxide==

Recent investigations suggest that complex I is a potent source of [[reactive oxygen species]].<ref name="pmid19061483">{{cite journal | vauthors = Murphy MP | title = How mitochondria produce reactive oxygen species | journal = The Biochemical Journal | volume = 417 | issue = 1 | pages = 1–13 | date = January 2009 | pmid = 19061483 | pmc = 2605959 | doi = 10.1042/BJ20081386 }}</ref> Complex I can produce [[superoxide]] (as well as [[hydrogen peroxide]]), through at least two different pathways. During forward electron transfer, only very small amounts of superoxide are produced (probably less than 0.1% of the overall electron flow).<ref name="pmid19061483"/><ref name="pmid9067806">{{cite journal | vauthors = Hansford RG, Hogue BA, Mildaziene V | title = Dependence of H2O2 formation by rat heart mitochondria on substrate availability and donor age | journal = Journal of Bioenergetics and Biomembranes | volume = 29 | issue = 1 | pages = 89–95 | date = February 1997 | pmid = 9067806 | doi = 10.1023/A:1022420007908 | s2cid = 7501110 }}</ref><ref>{{cite journal | vauthors = Stepanova A, Konrad C, Manfredi G, Springett R, Ten V, Galkin A | title = The dependence of brain mitochondria reactive oxygen species production on oxygen level is linear, except when inhibited by antimycin A | journal = Journal of Neurochemistry | volume = 148 | issue = 6 | pages = 731–745 | date = March 2019 | pmid = 30582748 | pmc = 7086484 | doi = 10.1111/jnc.14654 }}</ref>

During reverse electron transfer, complex I might be the most important site of superoxide production within mitochondria, with around 3-4% of electrons being diverted to superoxide formation.<ref name="Reverse electron transfer results i">{{cite journal | vauthors = Stepanova A, Kahl A, Konrad C, Ten V, Starkov AS, Galkin A | title = Reverse electron transfer results in a loss of flavin from mitochondrial complex I: Potential mechanism for brain ischemia reperfusion injury | journal = Journal of Cerebral Blood Flow and Metabolism | volume = 37 | issue = 12 | pages = 3649–3658 | date = December 2017 | pmid = 28914132 | pmc = 5718331 | doi = 10.1177/0271678X17730242 }}</ref> Reverse electron transfer, the process by which electrons from the reduced ubiquinol pool (supplied by [[succinate dehydrogenase]], [[glycerol-3-phosphate dehydrogenase]], [[electron-transferring flavoprotein]] or [[dihydroorotate dehydrogenase]] in mammalian mitochondria) pass through complex I to reduce NAD<sup>+</sup> to NADH, driven by the inner mitochondrial membrane potential electric potential. Although it is not precisely known under what pathological conditions reverse-electron transfer would occur in vivo, in vitro experiments indicate that this process can be a very potent source of superoxide when [[succinate]] concentrations are high and [[oxaloacetate]] or [[malate]] concentrations are low.<ref name="pmid17916065">{{cite journal | vauthors = Muller FL, Liu Y, Abdul-Ghani MA, Lustgarten MS, Bhattacharya A, Jang YC, Van Remmen H | title = High rates of superoxide production in skeletal-muscle mitochondria respiring on both complex I- and complex II-linked substrates | journal = The Biochemical Journal | volume = 409 | issue = 2 | pages = 491–9 | date = January 2008 | pmid = 17916065 | doi = 10.1042/BJ20071162 }}</ref> This can take place during tissue ischaemia, when oxygen delivery is blocked.<ref>{{cite journal | vauthors = Sahni PV, Zhang J, Sosunov S, Galkin A, Niatsetskaya Z, Starkov A, Brookes PS, Ten VS | display-authors = 6 | title = Krebs cycle metabolites and preferential succinate oxidation following neonatal hypoxic-ischemic brain injury in mice | journal = Pediatric Research | volume = 83 | issue = 2 | pages = 491–497 | date = February 2018 | pmid = 29211056 | pmc = 5866163 | doi = 10.1038/pr.2017.277 }}</ref>

Superoxide is a reactive oxygen species that contributes to cellular oxidative stress and is linked to neuromuscular diseases and aging.<ref name="pmid18307315">{{cite journal | vauthors = Esterházy D, King MS, Yakovlev G, Hirst J | title = Production of reactive oxygen species by complex I (NADH:ubiquinone oxidoreductase) from Escherichia coli and comparison to the enzyme from mitochondria | journal = Biochemistry | volume = 47 | issue = 12 | pages = 3964–71 | date = March 2008 | pmid = 18307315 | doi = 10.1021/bi702243b | doi-access = free }}</ref> NADH dehydrogenase produces superoxide by transferring one electron from FMNH<sub>2</sub> (or semireduced flavin) to oxygen (O<sub>2</sub>). The radical flavin leftover is unstable, and transfers the remaining electron to the iron-sulfur centers. It is the ratio of NADH to NAD<sup>+</sup> that determines the rate of superoxide formation.<ref name="pmid16682634">{{cite journal | vauthors = Kussmaul L, Hirst J | title = The mechanism of superoxide production by NADH:ubiquinone oxidoreductase (complex I) from bovine heart mitochondria | journal = Proceedings of the National Academy of Sciences of the United States of America | volume = 103 | issue = 20 | pages = 7607–12 | date = May 2006 | pmid = 16682634 | pmc = 1472492 | doi = 10.1073/pnas.0510977103 | bibcode = 2006PNAS..103.7607K | doi-access = free }}</ref><ref>{{cite journal | vauthors = Galkin A, Brandt U | title = Superoxide radical formation by pure complex I (NADH:ubiquinone oxidoreductase) from Yarrowia lipolytica | journal = The Journal of Biological Chemistry | volume = 280 | issue = 34 | pages = 30129–35 | date = August 2005 | pmid = 15985426 | doi = 10.1074/jbc.M504709200 | doi-access = free }}</ref>