The homeobox protein CEH-23 mediates prolonged longevity in response to impaired mitochondrial electron transport chain in C. elegans.
The homeobox protein CEH-23 mediates prolonged longevity in response to impaired mitochondrial electron transport chain in C. elegans.
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DOI：
10.1371/journal.pbio.1001084
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发表时间：
2011-06
期刊：
影响因子：
9.8
通讯作者：
Lee SS
中科院分区：
文献类型：
--
作者：
Walter L;Baruah A;Chang HW;Pace HM;Lee SS
最近的研究结果表明，线粒体电子传递链（METC）的扰动可以导致进化多样性生物体的寿命延长。为了揭示METC改变如何增加C. elegans，我们进行了RNAi筛选，并揭示了三个预测的转录因子是线粒体突变体延长寿命所特别需要的。特别是，我们证明了核同源盒蛋白CEH-23独特地介导寿命，但不是缓慢的发展，减少育雏大小，或抗氧化应激与线粒体突变。此外，我们表明ceh-23表达水平对改变的METC有反应，并且ceh-23的强制过表达足以延长野生型背景下的寿命。我们的数据表明，线粒体与细胞核的通讯是决定寿命的关键，并强调CEH-23是一种能够响应线粒体扰动的新型长寿因子。这些发现为线粒体如何影响衰老和年龄依赖性疾病提供了新的范例。长期以来，线粒体与衰老和年龄相关疾病有关。最近的研究表明，线粒体功能的轻微抑制可以显着增加各种生物体的寿命，这表明类似的机制可能在人类中起作用。然而，这种观察的分子基础在很大程度上是未知的。揭示允许改变线粒体功能以影响寿命的基因将为我们提供关于线粒体如何影响衰老过程的重要新见解，并将为未来旨在改善健康衰老和治疗年龄相关疾病的治疗发展铺平道路。在这里，我们在遗传模式生物C中使用了RNAi筛选。elegans，一种线虫，以揭示线粒体功能的改变如何调节寿命。我们发现，为了使线粒体影响寿命，它们必须与细胞核中的几个独特的转录因子进行通信。值得注意的是，我们发现，假定的同源框转录因子CEH-23，以前没有参与寿命的决定，能够响应线粒体功能的变化，从而导致寿命的延长。
Recent findings indicate that perturbations of the mitochondrial electron transport chain (METC) can cause extended longevity in evolutionarily diverse organisms. To uncover the molecular basis of how altered METC increases lifespan in C. elegans, we performed an RNAi screen and revealed that three predicted transcription factors are specifically required for the extended longevity of mitochondrial mutants. In particular, we demonstrated that the nuclear homeobox protein CEH-23 uniquely mediates the longevity but not the slow development, reduced brood size, or resistance to oxidative stress associated with mitochondrial mutations. Furthermore, we showed that ceh-23 expression levels are responsive to altered METC, and enforced overexpression of ceh-23 is sufficient to extend lifespan in wild-type background. Our data point to mitochondria-to-nucleus communications to be key for longevity determination and highlight CEH-23 as a novel longevity factor capable of responding to mitochondrial perturbations. These findings provide a new paradigm for how mitochondria impact aging and age-dependent diseases. Mitochondria have long been associated with aging and age-related diseases. Recent research has shown that a slight dampening of mitochondrial function can dramatically increase the lifespan of a wide range of organisms, suggesting that a similar mechanism likely operates in humans. The molecular basis of this observation is largely unknown, however. Uncovering the genes that allow altered mitochondrial function to impact longevity will give us important new insights into how mitochondria affect the aging process and will pave the way for future therapeutic developments aiming to improve healthy aging and to treat age-related diseases. Here, we used an RNAi screen in the genetic model organism C. elegans, a nematode worm, to uncover how altered mitochondrial function can modulate longevity. We found that in order for mitochondria to affect lifespan, they must communicate with several unique transcription factors in the nucleus. Notably, we discovered that the putative homeobox transcription factor CEH-23, which has not previously been implicated in longevity determination, is able to respond to changes in mitochondrial function and in turn causes an extension in lifespan.
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