Corson L B, Folmer J, Strain J J, Culotta V C, Cleveland D W
Predoctoral Program in Human Genetics, Johns Hopkins University, Baltimore, Maryland 21205, USA.
J Biol Chem. 1999 Sep 24;274(39):27590-6. doi: 10.1074/jbc.274.39.27590.
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.
本文表明，抗氧化酶铜锌超氧化物歧化酶（SOD1）的缺失会导致酿酒酵母中的液泡碎片化。野生型酵母有1 - 3个大液泡，而sod1Delta酵母有多达50个较小的液泡。这一碎片化是由氧气介导的证据包括以下发现：需氧（而非厌氧）生长的sod1Delta酵母表现出异常液泡，并且其他氧依赖性sod1缺失表型的遗传抑制子可挽救液泡缺陷。令人惊讶的是，铁也与碎片化过程有关，因为添加铁会加剧sod1Delta液泡缺陷，而铁饥饿则可改善该缺陷。由于据报道液泡是铁储存的场所，且铁与活性氧剧烈反应会产生有毒副产物，我们提出sod1Delta细胞中的液泡损伤源于液泡内铁介导的氧化增加，或源于可能与液泡配体非生产性结合的“游离”铁池增加。此外，sod1Delta细胞的其他多效性表型（包括对pH、营养剥夺和金属的敏感性增加）可能是液泡受损的继发结果。我们的发现支持氧化应激改变细胞铁稳态进而增加氧化损伤的假说。因此，我们的发现可能具有医学相关性，因为氧化应激和铁稳态改变都与多种人类疾病过程有关。我们的发现表明，降低细胞内铁的策略可能会显著减少氧化诱导的细胞损伤。
