Wicks Shawna, Bain Nathan, Duttaroy Atanu, Hilliker Arthur J, Phillips John P
Department of Molecular and Cellular Biology, University of Guelph, Guelph, ON N1G2W1, Canada.
Free Radic Biol Med. 2009 Jan 15;46(2):176-81. doi: 10.1016/j.freeradbiomed.2008.09.036. Epub 2008 Oct 17.
Oxidative stress is widely associated with disease and aging but the underlying mechanisms are incompletely understood. Here we show that the premature mortality of Drosophila deficient in superoxide scavengers, superoxide dismutase (SOD) 1 or SOD2, is rescued by chronic hypoxia. Strikingly, switching moribund SOD2-deficient adults from normoxia into hypoxia abruptly arrests their impending premature mortality and endows the survivors with a near-normal life span. This finding challenges the notion that irreversible oxidative damage initiated by unscavenged superoxide in the mitochondrial matrix underpins the premature mortality of SOD2-deficient adults. In contrast, switching moribund SOD1-deficient flies from normoxia into hypoxia fails to alter their mortality trajectory, suggesting that the deleterious effects of unscavenged superoxide in the cytoplasm/intermembrane space compartment are cumulative and largely irreversible. We conclude that cellular responses to superoxide-initiated oxidative stress are mediated through different compartment-specific pathways. Elucidating these pathways should provide novel insights into how aerobic cells manage oxidative stress in health, aging, and disease.
氧化应激与疾病和衰老广泛相关，但其潜在机制尚未完全明确。在此我们表明，缺乏超氧化物清除剂超氧化物歧化酶（SOD）1或SOD2的果蝇的过早死亡可通过慢性低氧得以挽救。令人惊讶的是，将濒死的SOD2缺陷成年果蝇从常氧环境转移至低氧环境会突然阻止其即将到来的过早死亡，并使存活者具有接近正常的寿命。这一发现挑战了线粒体基质中未清除的超氧化物引发的不可逆氧化损伤是SOD2缺陷成年果蝇过早死亡基础的观点。相反，将濒死的SOD1缺陷果蝇从常氧环境转移至低氧环境并不能改变其死亡轨迹，这表明细胞质/线粒体外膜间隙中未清除的超氧化物的有害影响是累积性的且在很大程度上是不可逆的。我们得出结论，细胞对超氧化物引发的氧化应激的反应是通过不同的特定区室途径介导的。阐明这些途径应能为需氧细胞在健康、衰老和疾病状态下如何应对氧化应激提供新的见解。
