Oxidative stress and iron are implicated in fragmenting vacuoles of Saccharomyces cerevisiae lacking Cu,Zn-superoxide dismutase

The absence of the antioxidant enzyme Cu,Zn-superoxide dismutase (SOD1) is shown here to cause vacuolar fragmentation in Saccharomyces cerevisiae. Wil d-type yeast have 1-3 large vacuoles whereas the sod1 Delta yeast have as m any as 50 smaller vacuoles. Evidence that this fragmentation is oxygen-medi ated includes the findings that aerobically (but not anaerobically) grown s od1 Delta yeast exhibit aberrant vacuoles and genetic suppressors of other oxygen-dependent sod1 null phenotypes rescue the vacuole defect. Surprising ly, iron also is implicated in the fragmentation process as iron addition e xacerbates the sod1 Delta vacuole defect while iron starvation ameliorates it. Because the vacuole is reported to be a site of iron storage and iron r eacts avidly with reactive oxygen species to generate toxic side products, we propose that vacuole damage in sod1 Delta cells arises from an elevation of iron-mediated oxidation within the vacuole or from elevated pools of "f ree" iron that may bind nonproductively to vacuolar ligands. Furthermore, a dditional pleiotropic phenotypes of sod1 Delta cells (including increased s ensitivity to pH, nutrient deprivation, and metals) may be secondary to vac uolar compromise. Our findings support the hypothesis that oxidative stress alters cellular iron homeostasis which in turn increases oxidative damage. Thus, our findings may have medical relevance as both oxidative stress and alterations in iron homeostasis have been implicated in diverse human dise ase processes. Our findings suggest that strategies to decrease intracellul ar iron may significantly reduce oxidatively induced cellular damage.