Saccharomyces cerevisiae exhibits a yAP-1-mediated adaptive response to malondialdehyde

Malondialdehyde (MDA) is a highly reactive aldehyde generally formed as a consequence of lipid peroxidation. MDA has been inferred to have mutagenic and cytotoxic roles and possibly to he a participant in the onset of atherosclerosis. Wild-type Saccharomyces cerevisiae acquires resistance to a lethal dose (5 mill) of MDA following prior exposure to a nonlethal concentration (1 mM). This response was completely inhibited by cycloheximide (50 mu g ml(-1)), indicating a requirement for protein synthesis for adaptation. Furthermore, we have examined the roles of glutathione (GSH), mitochondrial function, and yAP-1-mediated transcription in conferring resistance and adaptation to MDA. A yap1 disruption mutant exhibited the greatest sensitivity and was unable to adapt to MDA, implicating yAP-1 in both the adaptive response and constitutive survival. The effect of MDA on GSH mutants indicated a role for GSH in initial resistance, whereas resistance acquired through adaptation was independent of GSH, Likewise, respiratory mutants (petite mutants) were sensitive to MDA but were still able to mount an adaptive response similar to that of the wild type! excluding mitochondria from any role in adaptation. MDA was detected in yeast cells by the thiobarbituric acid test and subsequent high-pressure liquid chromatography separation, Elevated levels were detected following treatment with hydrogen peroxide. However, the MDA-adaptive response was independent of that to H2O2.