FARNESOL-INDUCED GENERATION OF REACTIVE OXYGEN SPECIES VIA INDIRECT INHIBITION OF THE MITOCHONDRIAL ELECTRON-TRANSPORT CHAIN IN THE YEAST SACCHAROMYCES-CEREVISIAE

The mechanism of farnesol (FOH)-induced growth inhibition of Saccharom yces cerevisiae was studied in terms of its promotive effect on genera tion of reactive oxygen species (ROS), The level of ROS generation in FOH-treated cells increased five- to eightfold upon the initial 30-min incubation, while cells treated with other isoprenoid compounds, like geraniol, geranylgeraniol, and squalene, showed no ROS-generating res ponse. The dependence of FOH-induced growth inhibition on such an oxid ative stress was confirmed by the protection against such growth inhib ition in the presence of an antioxidant such as cw-tocopherol, probuco l, or N-acetyl-cysteine, FOH could accelerate ROS generation only in c ells of the wild-type grande strain, not in those of the respiration-d eficient petite mutant ([rho(0)]), which illustrates the role of the m itochondrial electron transport chain as its origin, Among the respira tory chain inhibitors, ROS generation could be effectively eliminated with myxothiazol, which inhibits oxidation of ubiquinol to the ubisemi quinone radical by the Rieske iron-sulfur center of complex III, but n ot with antimycin A, an inhibitor of electron transport that is functi onal in further oxidation of the ubisemiquinone radical to ubiquinone in the Q cycle of complex III, Cellular oxygen consumption was inhibit ed immediately upon extracellular addition of FOH, whereas FOH and its possible metabolites failed to directly inhibit any oxidase activitie s detected with the isolated mitochondrial preparation. A protein kina se C (PKC) dependent mechanism was suggested to exist in the inhibitio n of mitochondrial electron transport since FOH-induced ROS generation could be effectively eliminated with a membrane-permeable diacylglyce rol analog which can activate PKC, The present study supports the idea that FOH inhibits the ability of the electron transport chain to acce lerate ROS production via interference with a phosphatidylinositol typ e of signal.