Effects of nitric oxide on the copper-responsive transcription factor Ace1 in Saccharomyces cerevisiae: cytotoxic and cytoprotective actions of nitric oxide.

Previous studies indicate that nitric oxide (NO) can serve as a regulator/disrupter of metal-metabolizing systems in cells and, indeed, this function may represent an important physiological and/or pathophysiological role for NO. In order to address possible mechanisms of this aspect of NO biology, the effect of NO on copper metabolism and toxicity in the yeast Saccharomyces cerevisiae was examined. Exposure of S. cerevisiae to NO resulted in an alteration of the activity of the copper-responsive transcription factor Acel. Low concentrations of the NO donor DEA/NO were found to slightly enhance copper-mediated activation of Acel. Since Acel regulates the expression of genes responsible for the protection of S. cerevisiae from metal toxicity, the effect of NO on the toxicity of copper toward S. cerevisiae was also examined. Interestingly, low concentrations of NO were also found to protect S. cerevisiae against the toxicity of copper. The effect of NO at high concentrations was, however, opposite. High concentrations of DEA/NO inhibited copper-mediated Acel activity. Correspondingly, high concentrations of DEA/NO (1 mM) dramatically enhanced copper toxicity. An intermediate concentration of DEA/NO (0.5 mM) exhibited a dual effect, enhancing toxicity at lower copper concentrations (<0.5 mM) and protecting at higher (> or =0.5 mM) copper concentrations. Thus, it is proposed that the ability of NO to both protect against (at low concentrations) and enhance (at high concentration) copper toxicity in S. cerevisiae is, at least partially, a result of its effect on Acel. The results of this study have implications for the role of NO as a mediator of metal metabolism.