Deletion of the mitochondrial superoxide dismutase sod-2 extends lifespan in Caenorhabditis elegans.
Deletion of the mitochondrial superoxide dismutase sod-2 extends lifespan in Caenorhabditis elegans.
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DOI：
10.1371/journal.pgen.1000361
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发表时间：
2009-02
期刊：
影响因子：
4.5
通讯作者：
Hekimi, Siegfried
中科院分区：
文献类型：
--
作者：
Van Raamsdonk, Jeremy M.;Hekimi, Siegfried
衰老的氧化应激理论假定，衰老源于正常代谢过程中产生的活性氧物质（ROS）所造成的分子损伤的积累。超氧化物歧化酶（SODs）通过清除超氧化物来抵消这一过程。先前已表明，在酵母、果蝇和小鼠中去除细胞质或线粒体的SOD会导致寿命缩短。在本实验中，我们研究了去除秀丽隐杆线虫中存在的五个单独的sod基因中的每一个所产生的影响。与在其他模式生物中观察到的情况相反，与野生型线虫相比，没有一个sod缺失突变体显示出寿命缩短，尽管对百草枯和胡桃醌诱导的氧化应激的敏感性明显增加。事实上，即使是缺失两个或三个sod基因组合的突变体，其存活时间至少与野生型线虫一样长。对这些突变体基因表达的检测显示其他sod基因有轻微的补偿性上调。有趣的是，我们发现sod - 2突变体尽管氧化损伤的蛋白质显著增加，但寿命却很长。测试sod - 2缺失对已知寿命延长途径的影响，揭示了与影响线粒体功能的基因存在明显的相互作用：sod - 2缺失显著延长了clk - 1线虫的寿命，同时明显缩短了isp - 1线虫的寿命。结合SOD - 2的线粒体定位以及sod - 2突变体线虫表现出长寿线粒体突变体所特有的表型——包括发育缓慢、繁殖力低和排便缓慢——这表明sod - 2的缺失通过类似的机制延长寿命。我们对sod - 2突变体线虫耗氧量降低的证明支持了这一结论。总体而言，我们表明由sod基因缺失引起的氧化应激增加并不会导致秀丽隐杆线虫寿命缩短，并且sod - 2的缺失通过改变线粒体功能延长了线虫的寿命。
在本文中，我们以秀丽隐杆线虫作为模型系统来研究衰老的氧化应激理论。该理论提出衰老源于活性氧物质（ROS）造成的分子损伤的积累。为了测试这一理论，我们研究了删除五个单独的超氧化物歧化酶（SOD）基因中的每一个对寿命和氧化应激敏感性的影响。由于SOD起到清除ROS的作用，氧化应激理论预测sod基因的缺失应该会增加氧化应激并缩短寿命。然而，与酵母、果蝇和小鼠不同，在这些生物中细胞质或线粒体SOD的缺失会导致寿命缩短，我们发现秀丽隐杆线虫中的sod缺失突变体尽管对氧化应激的敏感性增加，但没有一个表现出寿命缩短。令人惊讶的是，我们发现sod - 2突变体线虫寿命延长，甚至缺失主要的细胞质、线粒体和细胞外sod基因的线虫也能比野生型线虫活得更长。通过检测与其他已知延长寿命的基因的遗传相互作用，并将缺失sod - 2的线虫表型与已知的长寿线粒体突变体如clk - 1或isp - 1的表型进行比较，我们提供了证据表明sod - 2的缺失通过改变线粒体功能延长寿命。
The oxidative stress theory of aging postulates that aging results from the accumulation of molecular damage caused by reactive oxygen species (ROS) generated during normal metabolism. Superoxide dismutases (SODs) counteract this process by detoxifying superoxide. It has previously been shown that elimination of either cytoplasmic or mitochondrial SOD in yeast, flies, and mice results in decreased lifespan. In this experiment, we examine the effect of eliminating each of the five individual sod genes present in Caenorhabditis elegans. In contrast to what is observed in other model organisms, none of the sod deletion mutants shows decreased lifespan compared to wild-type worms, despite a clear increase in sensitivity to paraquat- and juglone-induced oxidative stress. In fact, even mutants lacking combinations of two or three sod genes survive at least as long as wild-type worms. Examination of gene expression in these mutants reveals mild compensatory up-regulation of other sod genes. Interestingly, we find that sod-2 mutants are long-lived despite a significant increase in oxidatively damaged proteins. Testing the effect of sod-2 deletion on known pathways of lifespan extension reveals a clear interaction with genes that affect mitochondrial function: sod-2 deletion markedly increases lifespan in clk-1 worms while clearly decreasing the lifespan of isp-1 worms. Combined with the mitochondrial localization of SOD-2 and the fact that sod-2 mutant worms exhibit phenotypes that are characteristic of long-lived mitochondrial mutants—including slow development, low brood size, and slow defecation—this suggests that deletion of sod-2 extends lifespan through a similar mechanism. This conclusion is supported by our demonstration of decreased oxygen consumption in sod-2 mutant worms. Overall, we show that increased oxidative stress caused by deletion of sod genes does not result in decreased lifespan in C. elegans and that deletion of sod-2 extends worm lifespan by altering mitochondrial function. In this paper, we examine the oxidative stress theory of aging using C. elegans as a model system. This theory proposes that aging results from the accumulation of molecular damage caused by reactive oxygen species (ROS). To test this theory, we examined the effect of deleting each of the five individual superoxide dismutase (SOD) genes on lifespan and sensitivity to oxidative stress. Since SOD acts to detoxify ROS, the oxidative stress theory predicts that deletion of sod genes should increase oxidative stress and decrease lifespan. However, in contrast to yeast, flies, and mice, where loss of either cytoplasmic or mitochondrial SOD results in decreased lifespan, we find that none of the sod deletion mutants in C. elegans exhibits a shortened lifespan despite increased sensitivity to oxidative stress. Surprisingly, we find that sod-2 mutant worms have extended lifespan and even worms with the primary cytoplasmic, mitochondrial, and extracellular sod genes deleted can live longer than wild-type worms. By examining genetic interactions with other genes known to extend lifespan and by comparing the phenotype of worms lacking sod-2 to that of known long-lived mitochondrial mutants such as clk-1 or isp-1, we provide evidence that the loss of sod-2 extends lifespan through alteration of mitochondrial function.
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影响因子：
7.4
作者：
De Castro, E;De Castro, SH;Johnson, TE
通讯作者：
Johnson, TE
DOI：
10.1111/j.1532-5415.1972.tb00787.x
发表时间：
1972-01-01
影响因子：
6.3
作者：
HARMAN, D
通讯作者：
HARMAN, D
影响因子：
4.4
作者：
Ichimiya, H;Huet, RG;Ishii, N
通讯作者：
Ishii, N
影响因子：
4.2
作者：
Johnson, TE;Henderson, S;Link, C
通讯作者：
Link, C
影响因子：
56.9
作者：
Ewbank, JJ;Barnes, TM;Hekimi, S
通讯作者：
Hekimi, S