The absence of the
antioxidant enzyme Cu,Zn-superoxide dismutase (SOD1) is shown here to cause vacuolar fragmentation in Saccharomyces cerevisiae. Wild-type yeast have 1-3 large vacuoles whereas the sod1Delta yeast have as many as 50 smaller vacuoles. Evidence that this fragmentation is
oxygen-mediated includes the findings that aerobically (but not anaerobically) grown sod1Delta yeast exhibit aberrant vacuoles and genetic suppressors of other
oxygen-dependent sod1 null phenotypes rescue the vacuole defect. Surprisingly,
iron also is implicated in the fragmentation process as
iron addition exacerbates the sod1Delta vacuole defect while
iron starvation ameliorates it. Because the vacuole is reported to be a site of
iron storage and
iron reacts avidly with
reactive oxygen species to generate toxic side products, we propose that vacuole damage in sod1Delta cells arises from an elevation of
iron-mediated oxidation within the vacuole or from elevated pools of "free"
iron that may bind nonproductively to vacuolar
ligands. Furthermore, additional pleiotropic phenotypes of sod1Delta cells (including increased sensitivity to pH, nutrient deprivation, and metals) may be secondary to vacuolar 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 disease processes. Our findings suggest that strategies to decrease intracellular
iron may significantly reduce oxidatively induced cellular damage.