Rotenone-Mediated Changes in Intracellular Coenzyme A Thioester Levels: Implications for Mitochondrial Dysfunction

[Image: see text] Rotenone, an organic pesticide and potent mitochondrial complex I inhibitor, causes Parkinson-like neurodegeneration in rodents and is implicated in human Parkinson’s disease. In this rapid report, rotenone induced a dose-dependent decrease in succinyl-coenzyme A (CoA) and increase in β-hydroxybutyryl-CoA in multiple human cell lines (IC(50) < 100 nM). Rotenone also inhibited [U-(13)C(6)]-glucose-derived [(13)C]-acetyl-CoA and [(13)C]-succinyl-CoA biosynthesis in SH-SY5Y neuroblastoma cells. These changes are compatible with a compensatory metabolic rearrangement. Stable isotope dilution liquid chromatography–mass spectrometry and CoA thioester isotopomer analysis provided insight into mechanisms of rotenone toxicity, which will facilitate the development of new biomarkers of mitochondrial dysfunction.