Mitochondrial superoxide acts in the intestine to extend longevity

Thomas Liontis, Megan M Senchuk, Shusen Zhu, Suleima Jacob-Tomas, Ulrich Anglas, Annika Traa, Sonja K Soo, Jeremy M. Van Raamsdonk
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Abstract

Reactive oxygen species (ROS) are highly reactive oxygen containing molecules that are generated by normal metabolism. While ROS can cause damage to the building blocks that make up cells, these molecules can also act as intracellular signals that promote longevity. The levels of ROS within the cell can be regulated by antioxidant enzymes, such as superoxide dismutase (SOD), which converts superoxide to hydrogen peroxide. Interestingly, our previous work has shown that disruption of the mitochondrial SOD gene sod-2 results in increased lifespan, indicating that elevating levels of mitochondrial superoxide can promote longevity. To explore the molecular mechanisms involved, we determined the tissues in which disruption of sod-2 is necessary for lifespan extension and the tissues in which disruption of sod-2 is sufficient to extend lifespan. We found that tissue-specific restoration of SOD-2 expression in worms lacking SOD-2 could partially revert changes in fertility, embryonic lethality and resistance to stress, but did not inhibit the effects of sod-2 deletion on lifespan. Knocking down sod-2 expression using RNA interference specifically in the intestine, but not other tissues, was sufficient to extend longevity. Intestine-specific knockdown of sod-2 also increased resistance to heat stress and while decreasing resistance to oxidative stress. Combined, these results indicate that disruption of sod-2 in neurons, intestine, germline, or muscle is not required for lifespan extension, but that decreasing sod-2 expression in just the intestine extends lifespan. This work defines the conditions required for elevated mitochondrial superoxide to increase longevity.
线粒体超氧化物在肠道中发挥作用延长寿命
活性氧(ROS)是正常新陈代谢产生的高活性含氧分子。虽然 ROS 会对构成细胞的基石造成损害,但这些分子也可以作为细胞内的信号,促进细胞的长寿。细胞内的 ROS 水平可由超氧化物歧化酶(SOD)等抗氧化酶调节,SOD 可将超氧化物转化为过氧化氢。有趣的是,我们之前的研究表明,破坏线粒体 SOD 基因 sod-2 会导致寿命延长,这表明提高线粒体超氧化物水平可以促进长寿。为了探索其中的分子机制,我们确定了在哪些组织中破坏 sod-2 是延长寿命所必需的,以及在哪些组织中破坏 sod-2 足以延长寿命。我们发现,在缺乏SOD-2的蠕虫中,组织特异性地恢复SOD-2的表达可以部分恢复生育能力、胚胎致死率和抗应激能力的变化,但并不能抑制sod-2缺失对寿命的影响。利用RNA干扰技术特异性地敲除肠道(而非其他组织)中的sod-2表达足以延长寿命。肠特异性敲除 sod-2 还能增强对热应激的抵抗力,同时降低对氧化应激的抵抗力。这些结果表明,在神经元、肠道、生殖细胞或肌肉中破坏sod-2并不是延长寿命的必要条件,但只在肠道中减少sod-2的表达却能延长寿命。这项工作确定了线粒体超氧化物升高延长寿命所需的条件。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
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