Pyruvate imbalance mediates metabolic reprogramming and mimics lifespan extension by dietary restriction in Caenorhabditis elegans
Pyruvate imbalance mediates metabolic reprogramming and mimics lifespan extension by dietary restriction in Caenorhabditis elegans
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DOI：
10.1111/j.1474-9726.2010.00640.x
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发表时间：
2011-02-01
期刊：
影响因子：
7.8
通讯作者：
Solari, Florence
中科院分区：
文献类型：
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作者：
Mouchiroud, Laurent;Molin, Laurent;Solari, Florence
限食是目前已知的延长动物寿命的最普遍的干预措施. DR还可以防止哺乳动物的肿瘤发展，这种作用需要肿瘤抑制因子PTEN。然而，作为DR有益作用基础的代谢和细胞过程知之甚少。我们在RNAi筛选中鉴定了slcf-1，以寻找以PTEN/daf-18依赖性方式延长秀丽隐杆线虫寿命的基因。我们发现，slcf-1突变，增加了40%的平均寿命，模仿DR的蠕虫喂养随意。slcf-1突变体的基于NMR的代谢组学表征显示，与野生型动物相比，脂质水平较低，正如饮食限制动物所预期的那样，但丙酮酸含量也较高。上位性实验和代谢测量支持一个模型，其中slcf-1突变体的长寿命依赖于线粒体丙酮酸代谢增加，再加上对氧化应激的适应性反应。这种反应需要ESTA-18/PTEN和先前鉴定的DR效应物PHA-4/FOXA、HSF-1/HSF 1、SIR-2.1/SIRT-1和AMPK/AAK-2。总的来说，我们的数据表明丙酮酸稳态在C.并且DR的有益作用来自于涉及线粒体的激素机制。SLCF-1蛋白序列的分析预测，slcf-1编码属于保守的单羧酸转运蛋白家族的质膜转运蛋白。这些发现表明，在哺乳动物中抑制这种转运蛋白同源物也可能促进DR反应。
P>Dietary restriction (DR) is the most universal intervention known to extend animal lifespan. DR also prevents tumor development in mammals, and this effect requires the tumor suppressor PTEN. However, the metabolic and cellular processes that underly the beneficial effects of DR are poorly understood. We identified slcf-1 in an RNAi screen for genes that extend Caenorhabditis elegans lifespan in a PTEN/daf-18-dependent manner. We showed that slcf-1 mutation, which increases average lifespan by 40%, mimics DR in worms fed ad libitum. An NMR-based metabolomic characterization of slcf-1 mutants revealed lower lipid levels compared to wild-type animals, as expected for dietary-restricted animals, but also higher pyruvate content. Epistasis experiments and metabolic measurements support a model in which the long lifespan of slcf-1 mutants relies on increased mitochondrial pyruvate metabolism coupled to an adaptive response to oxidative stress. This response requires DAF-18/PTEN and the previously identified DR effectors PHA-4/FOXA, HSF-1/HSF1, SIR-2.1/SIRT-1, and AMPK/AAK-2. Overall, our data show that pyruvate homeostasis plays a central role in lifespan control in C. elegans and that the beneficial effects of DR results from a hormetic mechanism involving the mitochondria. Analysis of the SLCF-1 protein sequence predicts that slcf-1 encodes a plasma membrane transporter belonging to the conserved monocarboxylate transporter family. These findings suggest that inhibition of this transporter homolog in mammals might also promote a DR response.