RNA interference-mediated silencing of Sod2 in Drosophila leads to early adult-onset mortality and elevated endogenous oxidative stress
RNA interference-mediated silencing of Sod2 in Drosophila leads to early adult-onset mortality and elevated endogenous oxidative stress
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DOI：
10.1073/pnas.252342899
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发表时间：
2002-12-10
影响因子：
11.1
通讯作者：
Phillips, JP
中科院分区：
文献类型：
--
作者：
Kirby, K;Hu, JG;Phillips, JP
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，线粒体定位的超氧化物歧化酶(SOD)2被认为在对抗衰老相关的氧化应激中发挥着重要的一线防御作用。虽然对SOD1缺失突变的遗传学研究有助于阐明果蝇衰老过程中反应氧代谢的作用，但Sod2基因突变的缺乏阻碍了对这种重要抗氧化酶在果蝇衰老模型中参与的同等分析。在这里，我们报告了通过表达GAL4调节的、反向重复的Sod2 RNA干扰转基因在其他正常动物中去除线粒体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基本酶组分的丧失，增强对外部氧化应激的敏感性，并导致年轻成人的早发性死亡。与之形成鲜明对比的是，消融SOD2对幼虫和蛹的发育没有明显的影响，这可能反映了从幼虫到成虫的变态过程中氧利用和/或活性氧代谢的根本转变。
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 and/or reactive oxygen metabolism that occurs during metamorphosis from larval to adult life.