Piericidin A

Complex I, also known as NADH:ubiquinone oxidoreductase or NADH dehydrogenase (ubiquinone), catalyzes the transfer of electrons from NADH to ubiquinone (also known as coenzyme Q₁₀) as part of the respiratory chain leading to ATP generation. Piericidin A is an irreversible inhibitor of mitochondrial complex I that strongly associates with ubiquinone binding sites in both mitochondrial and bacterial forms of the enzyme.^1,2 First identified as an insecticidal metabolite produced by Streptomyces, piericidin A was soon found to bind and inhibit complex I at nanomolar concentrations.^3,4 The inhibition of complex I by piericidin A in the presence of NADH results in the generation of reactive oxygen species.⁵ In plants, pieridicin A inhibits photosystem II, a water-plastoquinone oxidoreductase involved in light-dependent electron transfer.⁶ Piericidin A also suppresses the up-regulation of the glucose-regulated protein GRP78 in glucose-deprived, etoposide-resistant HT-29 cells, resulting in cell death (IC₅₀ = 7.7 nM).⁷

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1. Hatefi, Y. Flavoproteins of the electron transport system and the site of action of amytal, rotenone, and piericidin A. Proc. Natl. Acad. Sci. USA 60(2), 733-740 (1968).

2. Melo, A.M.P., Bandeiras, T.M., and Teixeira, M. New insights into type II NAD(P)H:quinone oxidoreductases. Microbiol. Mol. Biol. Rev. 68(4), 603-616 (2004).

3. Takahashi, N., Suzuki, A., and Tamura, S. Structure of piericidin A. J. Am. Chem. Soc. 87(9), 2066-2068 (1965).

4. Horgan, D.J., and Casida, J.E. Specific binding of [¹⁴C] piericidin A in the reduced nicotinamide--adenine dinucleotide dehydrogenase segment of the mitochondrial respiratory chain. Biochem. J. 108(1), 153-154 (1968).

5. Fato, R., Bergamini, C., Bortolus, M., et al. Differential effects of mitochondrial Complex I inhibitors on production of reactive oxygen species. Biochim. Biophys. Acta 1787(5), 384-392 (2009).

6. Ikezawa, N., Ifuku, K., Endo, T., et al. Inhibition of photosystem II of spinach by the respiration inhibitors piericidin A and thenoyltrifluoroacetone. Biosci. Biotechnol. Biochem. 66(9), 1925-1929 (2002).

7. Hwang, J.H., Kim, J.Y., Cha, M.R., et al. Etoposide-resistant HT-29 human colon carcinoma cells during glucose deprivation are sensitive to piericidin A, a GRP78 down-regulator. J. Cell Physiol. 215(1), 243-250 (2008).