Modulation of fluconazole sensitivity by the interaction of mitochondria and Erg3p in Saccharomyces cerevisiae

We studied the effects of fluconazole, an ergosterol-depleting agent, in Sa ccharomyces cerevisiae, a genetically tractable fungus closely related to C andida albicans. The wild-type Saccharomyces strain was sensitive to flucon azole, but the isogenic cytoplasmic petite mutant (rho(-)) was resistant. T he mechanism of resistance of rho(-) mutants appeared to involve uncoupling of oxidative phosphorylation. However, the petite strain with a mutation i n Delta 5,6 desaturase (erg3 rho(-)) was sensitive to fluconazole, in contr ast to its erg3 rho* counterpart. It is known that erg3 mutants are azole r esistant through the accumulation of 14-methyl-fecosterol, a less toxic erg osterol Intermediate. These results indicate that mitochondria function as important physiological partners with Erg3p in the accumulation of toxic st erol intermediates In the presence of azoles.