text: Bullatacin (an acetogenin found in Asimina triloba fruit) is the most potent known inhibitor of NADH dehydrogenase (ubiquinone) (=1.2 nM, stronger than rotenone). The best-known inhibitor of complex I is rotenone (commonly used as an organic pesticide). Rotenone and rotenoids 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. 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.
  Acetogenins 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. Rolliniastatin-2, an acetogenin, is the first complex I inhibitor found that does not share the same binding site as rotenone.
  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.
  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. 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.
  Inhibition of complex I has been implicated in hepatotoxicity associated with a variety of drugs, for instance flutamide and nefazodone. Further, complex I inhibition was shown to trigger NAD-independent glucose catabolism.