Editing Respiratory complex I (section)

==Inhibitors==
Inhibition of complex I is the mode of action of the METI acaricides and insecticides: fenazaquin, fenpyroximate, pyrimidifen, pyridaben, [[tebufenpyrad]], and tolfenpyrad.<ref name=":02">{{Cite book |last=Jeschke |first=Peter |url=https://onlinelibrary.wiley.com/doi/book/10.1002/9783527699261 |title=Modern Crop Protection Compounds |last2=Witschel |first2=Matthias |last3=Krämer |first3=Wolfgang |last4=Schirmer |first4=Ulrich |date=25 January 2019 |publisher=Wiley‐VCH |isbn=9783527699261 |edition=3rd |pages=1156-1201 |chapter=32.3 Inhibitors of Mitochondrial Electron Transport: Acaricides and Insecticides}}</ref><ref>{{Cite journal |last=Bajda |first=Sabina |last2=Dermauw |first2=Wannes |last3=Panteleri |first3=Rafaela |last4=Sugimoto |first4=Naoya |date=January 2017 |title=A mutation in the PSST homologue of complex I (NADH:ubiquinone oxidoreductase) from Tetranychus urticae is associated with resistance to METI acaricides |url=https://doi.org/10.1016/j.ibmb.2016.11.010 |journal=Insect Biochemistry and Molecular Biology |volume=80 |pages=79-90 |issn=0965-1748}}</ref><ref>{{Cite journal |last=De Rouck |first=Sander |last2=İnak |first2=Emre |last3=Dermauw |first3=Wannes |last4=Van Leeuwen |first4=Thomas |date=August 2023 |title=A review of the molecular mechanisms of acaricide resistance in mites and ticks |url=https://doi.org/10.1016/j.ibmb.2023.103981 |journal=Insect Biochemistry and Molecular Biology |volume=159 |pages=103981 |issn=0965-1748}}</ref> They are assigned to [[Insecticide Resistance Action Committee#Table of modes of action and classes of insecticide|IRAC]] group 21A. Perhaps the best-known inhibitor of complex I is [[rotenone]], which is used as a piscicide and previously commonly used as an organic pesticide, but now banned in many countries. It is in IRAC group 21B. Rotenone and [[rotenoid]]s are [[isoflavonoids]] occurring in several genera of tropical plants such as Antonia (''[[Loganiaceae]]''), [[Derris]] and [[Lonchocarpus]] (''[[Faboideae]]'', ''[[Fabaceae]]''). There have been reports of the indigenous people of French Guiana using rotenone-containing plants to fish - due to its ichthyotoxic effect - as early as the 17th century.<ref name="pmid7132401">{{cite journal | vauthors = Moretti C, Grenand P | title = [The "nivrées", or ichthyotoxic plants of French Guyana] | language = fr | journal = Journal of Ethnopharmacology | volume = 6 | issue = 2 | pages = 139–60 | date = September 1982 | pmid = 7132401 | doi = 10.1016/0378-8741(82)90002-2 }}</ref> Rotenone binds to the [[ubiquinone]] binding site of complex I as well as [[piericidin A]], another potent inhibitor with a close structural homologue to ubiquinone.

[[Acetogenin]]s from [[Annonaceae]] are even more potent inhibitors of complex I. They cross-link to the ND2 subunit, which suggests that ND2 is essential for quinone-binding.<ref name="pmid20074573">{{cite journal|vauthors=Nakamaru-Ogiso E, Han H, Matsuno-Yagi A, Keinan E, Sinha SC, Yagi T, Ohnishi T|date=March 2010|title=The ND2 subunit is labeled by a photoaffinity analogue of asimicin, a potent complex I inhibitor|journal=FEBS Letters|volume=584|issue=5|pages=883–8|doi=10.1016/j.febslet.2010.01.004|pmc=2836797|pmid=20074573}}</ref> Rolliniastatin-2, an acetogenin, is the first complex I inhibitor found that does not share the same binding site as rotenone.<ref name="pmid 8037664">{{cite journal | vauthors = Degli Esposti M, Ghelli A, Ratta M, Cortes D, Estornell E | title = Natural substances (acetogenins) from the family Annonaceae are powerful inhibitors of mitochondrial NADH dehydrogenase (Complex I) | journal = The Biochemical Journal | volume = 301 | pages = 161–7 | date = July 1994 | issue = Pt 1 | pmid = 8037664 | pmc = 1137156 | doi =  10.1042/bj3010161}}</ref> [[Bullatacin]] (an [[acetogenin]] found in ''[[Asimina triloba]]'' fruit) is the most potent known inhibitor of NADH dehydrogenase (ubiquinone) ({{IC50}}=1.2 nM, stronger than rotenone).<ref name="pmid9711297">{{cite journal |vauthors=Miyoshi H, Ohshima M, Shimada H, Akagi T, Iwamura H, McLaughlin JL |date=July 1998 |title=Essential structural factors of annonaceous acetogenins as potent inhibitors of mitochondrial complex I |journal=Biochimica et Biophysica Acta (BBA) - Bioenergetics |volume=1365 |issue=3 |pages=443–52 |doi=10.1016/s0005-2728(98)00097-8 |pmid=9711297 |doi-access=free}}</ref> 

Despite more than 50 years of study of complex I, no inhibitors blocking the electron flow inside the enzyme have been found. Hydrophobic inhibitors like rotenone or piericidin most likely disrupt the electron transfer between the terminal FeS cluster N2 and ubiquinone. It has been shown that long-term systemic inhibition of complex I by rotenone can induce selective degeneration of dopaminergic neurons.<ref name="pmid18599602 ">{{cite journal | vauthors = Watabe M, Nakaki T | title = Mitochondrial complex I inhibitor rotenone inhibits and redistributes vesicular monoamine transporter 2 via nitration in human dopaminergic SH-SY5Y cells | journal = Molecular Pharmacology | volume = 74 | issue = 4 | pages = 933–40 | date = October 2008 | pmid = 18599602 | doi = 10.1124/mol.108.048546 | s2cid = 1844073 }}</ref>

Complex I is also blocked by [[adenosine diphosphate ribose]] – a reversible [[competitive inhibitor]] of NADH oxidation – by binding to the enzyme at the nucleotide binding site.<ref name="pmid 9230920">{{cite journal | vauthors = Zharova TV, Vinogradov AD | title = A competitive inhibition of the mitochondrial NADH-ubiquinone oxidoreductase (complex I) by ADP-ribose | journal = Biochimica et Biophysica Acta (BBA) - Bioenergetics | volume = 1320 | issue = 3 | pages = 256–64 | date = July 1997 | pmid = 9230920 | doi = 10.1016/S0005-2728(97)00029-7 | doi-access = free }}</ref> Both hydrophilic NADH and hydrophobic ubiquinone analogs act at the beginning and the end of the internal electron-transport pathway, respectively.

The antidiabetic drug [[Metformin]] has been shown to induce a mild and transient inhibition of the mitochondrial respiratory chain complex I, and this inhibition appears to play a key role in its mechanism of action.<ref name="pmid 22117616">{{cite journal | vauthors = Viollet B, Guigas B, Sanz Garcia N, Leclerc J, Foretz M, Andreelli F | title = Cellular and molecular mechanisms of metformin: an overview | journal = Clinical Science | volume = 122 | issue = 6 | pages = 253–70 | date = March 2012 | pmid = 22117616 | pmc = 3398862 | doi = 10.1042/CS20110386 | url = http://www.hal.inserm.fr/inserm-00658070/document }}</ref>

Inhibition of complex I has been implicated in [[hepatotoxicity]] associated with a variety of drugs, for instance [[flutamide]] and [[nefazodone]].<ref name="NadanacivaWill2011">{{cite journal | vauthors = Nadanaciva S, Will Y | title = New insights in drug-induced mitochondrial toxicity | journal = Current Pharmaceutical Design | volume = 17 | issue = 20 | pages = 2100–12 | year = 2011 | pmid = 21718246 | doi = 10.2174/138161211796904795 }}</ref> Further, complex I inhibition was shown to trigger NAD<sup>+</sup>-independent [[glucose]] catabolism.<ref>{{Cite journal |last=Abrosimov |first=Roman |last2=Baeken |first2=Marius W. |last3=Hauf |first3=Samuel |last4=Wittig |first4=Ilka |last5=Hajieva |first5=Parvana |last6=Perrone |first6=Carmen E. |last7=Moosmann |first7=Bernd |date=2024-01-25 |title=Mitochondrial complex I inhibition triggers NAD+-independent glucose oxidation via successive NADPH formation, “futile” fatty acid cycling, and FADH2 oxidation |url=https://doi.org/10.1007/s11357-023-01059-y |journal=GeroScience |language=en |doi=10.1007/s11357-023-01059-y |issn=2509-2723|doi-access=free |pmc=11226580 }}</ref>