Effect of polygodial on the mitochondrial ATPase of Saccharomyces cerevisiae

The fungicidal mechanism of a naturally occurring sesquiterpene dialdehyde, polygodial, was investigated in Saccharomyces cerevisiae. In an acidificat ion assay, polygodial completely suppressed the glucose-induced decrease in external pH at 3.13 mu g/ml, the same as the fungicidal concentration. Aci dification occurs primarily through the proton-pumping action of the plasma membrane ATPase, Pma1p, Surprisingly, this ATPase was not directly inhibit ed by polygodial, In contrast, the two other membrane-bound ATPases in yeas t were found to be susceptible to the compound, The mitochondrial ATPase wa s inhibited by polygodial in a dose-dependent manner at concentrations simi lar to the fungicidal concentration, whereas the vacuolar ATPase was only s lightly inhibited, Cytoplasmic petite mutants, which lack mitochondrial DNA and are respiration deficient, were significantly less susceptible to poly godial than the wild type, as was shown in time-kill curves. A pet9 mutant which lacks a functional ADP-ATP translocator and is therefore respiration dependent was rapidly inhibited by polygodial, The results of these suscept ibility assays link enzyme inhibition to physiological effect, previous stu dies have reported that plasma membrane disruption is the mechanism of poly godial-induced cell death; however, these results support a more complex pi cture of its effect. A major target of polygodial in yeast is mitochondrial ATP synthase, Reduction of the ATP supply leads to a suppression of Pma1 A TPase activity and impairs adaptive responses to other facets of polygodial 's cellular inhibition.