Kirby Kim, Hu Jianguo, Hilliker Arthur J, Phillips John P
Department of Molecular Biology and Genetics, University of Guelph, Guelph, ON, Canada N1G 2W1.
Proc Natl Acad Sci U S A. 2002 Dec 10;99(25):16162-7. doi: 10.1073/pnas.252342899. Epub 2002 Nov 27.
Oxidative stress has been widely implicated as an important factor in the aging process. Because mitochondrial respiration is the principal source of reactive oxygen within cells, the mitochondrially localized superoxide dismutase (SOD) 2 is thought to play an important front-line defensive role against aging-related oxidative stress. Although genetic studies with mutants deficient in SOD1, the predominantly cytosolic isoform of SOD, have been instrumental in elucidating the role of reactive oxygen metabolism in aging in Drosophila, the lack of available mutations in the Sod2 gene has hampered an equivalent analysis of the participation of this important antioxidant enzyme in the Drosophila aging model. Here we report that ablation of mitochondrial SOD2 through expression of a GAL4-regulated, inverted-repeat Sod2 RNA-interference transgene in an otherwise normal animal causes increased endogenous oxidative stress, resulting in loss of essential enzymatic components of the mitochondrial respiratory chain and the tricarboxylic acid cycle, enhances sensitivity to applied oxidative stress, and causes early-onset mortality in young adults. In sharp contrast, ablation of SOD2 has no overt effect on the development of larvae and pupae, which may reflect a fundamental transition in oxygen utilization andor reactive oxygen metabolism that occurs during metamorphosis from larval to adult life.
氧化应激被广泛认为是衰老过程中的一个重要因素。由于线粒体呼吸是细胞内活性氧的主要来源，定位于线粒体的超氧化物歧化酶（SOD）2被认为在抵御与衰老相关的氧化应激方面发挥着重要的一线防御作用。尽管对缺乏SOD1（SOD的主要胞质同工型）的突变体进行的遗传学研究有助于阐明果蝇衰老过程中活性氧代谢的作用，但Sod2基因缺乏可用的突变阻碍了对这种重要抗氧化酶在果蝇衰老模型中参与情况的等效分析。在此我们报告，通过在其他方面正常的动物中表达GAL4调控的反向重复Sod2 RNA干扰转基因来消除线粒体SOD2，会导致内源性氧化应激增加，导致线粒体呼吸链和三羧酸循环的必需酶成分丧失，增强对施加的氧化应激的敏感性，并导致年轻成虫过早死亡。与之形成鲜明对比的是，消除SOD2对幼虫和蛹的发育没有明显影响，这可能反映了从幼虫到成虫变态过程中发生的氧利用和/或活性氧代谢的根本转变。
