Farnesol-Induced Generation of Reactive Oxygen Species via Indirect Inhibition of the Mitochondrial Electron Transport Chain in the Yeast Saccharomyces cerevisiae

Abstract

The mechanism of farnesol (FOH)-induced growth inhibition ofSaccharomyces cerevisiae was studied in terms of its promotive effect on generation 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 response. The dependence of FOH-induced growth inhibition on such an oxidative stress was confirmed by the protection against such growth inhibition in the presence of an antioxidant such as α-tocopherol, probucol, orN-acetylcysteine. FOH could accelerate ROS generation only in cells of the wild-type grande strain, not in those of the respiration-deficient petite mutant ([rho 0]), which illustrates the role of the mitochondrial electron transport chain as its origin. Among the respiratory chain inhibitors, ROS generation could be effectively eliminated with myxothiazol, which inhibits oxidation of ubiquinol to the ubisemiquinone radical by the Rieske iron-sulfur center of complex III, but not with antimycin A, an inhibitor of electron transport that is functional in further oxidation of the ubisemiquinone radical to ubiquinone in the Q cycle of complex III. Cellular oxygen consumption was inhibited immediately upon extracellular addition of FOH, whereas FOH and its possible metabolites failed to directly inhibit any oxidase activities detected with the isolated mitochondrial preparation. A protein kinase C (PKC)-dependent mechanism was suggested to exist in the inhibition of mitochondrial electron transport since FOH-induced ROS generation could be effectively eliminated with a membrane-permeable diacylglycerol analog which can activate PKC. The present study supports the idea that FOH inhibits the ability of the electron transport chain to accelerate ROS production via interference with a phosphatidylinositol type of signal.

Cytological evaluation of the effect of azoxystrobin and alternative oxidase inhibitors in Botrytis cinerea

“…Moreover, the farnesol-induced apoptosis was associated with mitochondrial generation of ROS in A. nidulans and yeast (Machida et al, 1998;Semighini et al, 2006). However, the farnesol generated ROS indirectly via the PKC signalling cascade (Machida et al, 1998). This complicated mode of action of farnesol seems to be different from that of QoI fungicides, which bind directly to the Qo portion of cytochrome bc 1 complex (Becker et al, 1981).…”

“…In Penicillium digitatum, oxidative stress produced by exogenous treatment with hydrogen peroxide caused ultrastructural disorganization (Cerioni et al, 2010). Moreover, in Aspergillus nidulans and yeast, farnesol-induced apoptosis participated in mitochondrial generation of ROS (Machida et al, 1998;Semighini et al, 2006). In Botrytis cinerea, the presence of dead cells following treatment with AZ and PG was confirmed by vital indicator, calcein-AM (acetoxymethyl ester), and nucleus staining (Takahashi et al, 2008).…”

Dolichol biosynthesis in the yeast : an insight into the regulatory role of farnesyl diphosphate synthase

“…Moreover, farnesol has been shown to cause apoptotic death of human acute leukaemia cells [39,40] and growth inhibition of S. cerevisiae due to generation of reactive oxygen species [42], thus con¢rming the complexity of the regulatory e¡ect of FPP and its derivatives.…”

New approaches in bioprocess‐control: Consortium guidance by synthetic cell‐cell communication based on fungal pheromones

“…Likewise, some fungi secrete small molecules to combat potentially competing species. C. albicans is known to secrete farnesol as a quorum sensing molecule, which was reported to induce cell death in several yeasts and fungi, thereby favoring survival and spread of C. albicans [109][110][111][112][113]. Introducing detoxification mechanisms (e.g.…”