Rotenone (CAS: 83-79-4)

C₂₃H₂₂O₆

• Cell permeable reversible and competitive mitochondrial electron transport chain complex I (NADH-CoQ reductase) inhibitor (IC₅₀=1.7-2.2μM).
• Inhibits NADH/DB oxidoreductase and NADH oxidase and consequently oxidative phosphorylation (OXPHOS). Specifically inhibits NAD-linked substrate oxidation of NADH dehydrogenase.
• Useful agent for immunometabolism research. Inhibition of electron transport chain in mitochondria leads to blocking of the transfer of electrons from iron-sulfur centers in complex I to ubiquinone. This interferes with NADH during the creation of usable cellular energy (ATP), and Complex I is unable to pass off its electron to CoQ, creating a back-up of electrons within the mitochondrial matrix. Cellular oxygen is reduced to the radical, creating reactive oxygen species, which can damage DNA and other components of the mitochondria.
• Shown to inhibit mammalian cell proliferation, via suppressing microtubule assembly by binding to tubulin and inhibiting autophagy induction, by blocking lysosomal degradation of autophagic vacuoles.
• Shown to induce cell cycle arrest and apoptosis through production of mitochondrial ROS, consequently leading to induction of oxidative stress.
• Used to induce Parkinson's diseases-like syndrome in experimental animal model.
• Selective priming signal for NLRP3 inflammasome activation in combination with ATP, but not with Nigericin or MSU.
• Commonly used as a broad spectrum insecticide, piscicide and pesticide.

1. Rotenone, an anticarcinogen, inhibits cellular proliferation but not peroxisome proliferation in mouse liver: M.L. Cunningham, et al.; Cancer Lett. 95, 93 (1995)
2. Rotenone-induced G2/M cell cycle arrest and apoptosis in a human B lymphoma cell line PW: J.S. Armstrong, et al.; BBRC 289, 973 (2001)
3. Mitochondrial complex I inhibitor rotenone induces apoptosis through enhancing mitochondrial reactive oxygen species production: N. Li, et al.; J. Biol. Chem. 278, 8516 (2003)
4. Rotenone induces cell death in primary dopaminergic culture by increasing ROS production and inhibiting mitochondrial respiration: K. Radad, et al.; Neurochem. Int. 49, 379 (2006)
5. Rotenone inhibits mammalian cell proliferation by inhibiting microtubule assembly through tubulin binding: P. Srivastava & D. Panda; FEBS J. 274, 4788 (2007)
6. Pesticides and impairment of mitochondrial function in relation with the parkinsonian syndrome: C. Gomez, et al.; Front. Biosci. 12, 1079 (2007)
7. Mechanisms of rotenone-induced proteasome inhibition: A.P. Chou, et al.; Neurotoxicol. 31, 367 (2010)
8. Rotenone inhibits autophagic flux prior to inducing cell death: B.J. Mader, et al.; ACS Chem. Neurosci. 3, 1063 (2012)
9. Mitochondrial complex I inhibitor rotenone-induced toxicity and its potential mechanisms in Parkinson's disease models: N. Xiong, et al.; Crit. Rev. Toxicol. 42, 613 (2012) (Review)
10. Rotenone-induced oxidative stress and apoptosis in human liver HepG2 cells: M.A. Siddiqui, et al.; Mol. Cell Biochem. 384, 59 (2013)
11. The rotenone model of Parkinson's disease: genes, environment and mitochondria: J.T. Greenamyre, et al.; Parkinsonism Relat. Disord. 9, S59 (2013) (Review)
12. Metabolome and proteome profiling of complex I deficiency induced by rotenone: I. Gielisch, & D. Meierhofer ; J. Proteome Res. 14, 224 (2015)
13. Rotenone-induced Impairment of Mitochondrial Electron Transport Chain Confers a Selective Priming Signal for NLRP3 Inflammasome Activation: J.H. Won, et al.; J. Biol. Chem. 290, 27425 (2015)
14. Succinate Dehydrogenase Supports Metabolic Repurposing of Mitochondria to Drive Inflammatory Macrophages: E.L. Mills, et al.; Cell 167, 457 (2016)
15. A guide to immunometabolism for immunologists: L.A. O'Neill, et al.; Nat. Rev. Immunol. 16, 553 (2016)
16. The respiratory chain inhibitor rotenone affects peroxisomal dynamics via its microtubule-destabilising activity: J.B. Passmore, et al.; Histochem. Cell Biol. 148, 331 (2017)