Malate and fumarate extend lifespan in Caenorhabditis elegans.
Malate and fumarate extend lifespan in Caenorhabditis elegans.
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DOI：
10.1371/journal.pone.0058345
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发表时间：
2013
期刊：
影响因子：
3.7
通讯作者：
Bradshaw PC
中科院分区：
文献类型：
--
作者：
Edwards CB;Copes N;Brito AG;Canfield J;Bradshaw PC
三羧酸（TCA）循环代谢产物苹果酸可延长线虫的寿命和耐热性。优美的苹果酸可以通过酶脱氢酶从富马酸合成，并通过苹果酸脱氢酶进一步氧化为草酰乙酸，伴随着NAD的还原。此外，富马酸也延长了寿命，但琥珀酸除了没有，虽然所有三个中间体激活细胞保护性转录因子的核转位和保护百草枯诱导的氧化应激。乙醛酸分流，一种与C寿命延长相关的合成代谢途径。elegans可逆地将异柠檬酸和乙酰辅酶A转化为琥珀酸、苹果酸和辅酶A。苹果酸盐添加所提供的寿命增加并未发生在琥珀酸脱氢酶（fum-1）、乙醛酸分流（gei-7）、琥珀酸脱氢酶黄素蛋白（sdha-2）或可溶性延胡索酸还原酶F48 E8.3 RNAi敲减蠕虫中。因此，为了延长寿命，苹果酸必须首先转化为富马酸，然后富马酸必须通过可溶性富马酸还原酶和线粒体电子传递链复合物II还原为琥珀酸。富马酸盐还原为琥珀酸盐与FADH 2氧化为FAD偶联。由苹果酸诱导的寿命延长依赖于寿命调节因子α-16和SIR-2.1。补充苹果酸并没有延长长寿的eat-2突变蠕虫的寿命，这是一种饮食限制模型。此外，苹果酸和富马酸增加耗氧量，但降低ATP水平和线粒体膜电位表明氧化磷酸化的轻度解偶联。苹果酸还增加NADPH、NAD和NAD/NADH比率。富马酸盐还原、乙醛酸分流活性和轻度线粒体解偶联可能通过增加氧化NAD和FAD辅因子的量而促进苹果酸盐和富马酸盐诱导的寿命延长。
Malate, the tricarboxylic acid (TCA) cycle metabolite, increased lifespan and thermotolerance in the nematode C. elegans. Malate can be synthesized from fumarate by the enzyme fumarase and further oxidized to oxaloacetate by malate dehydrogenase with the accompanying reduction of NAD. Addition of fumarate also extended lifespan, but succinate addition did not, although all three intermediates activated nuclear translocation of the cytoprotective DAF-16/FOXO transcription factor and protected from paraquat-induced oxidative stress. The glyoxylate shunt, an anabolic pathway linked to lifespan extension in C. elegans, reversibly converts isocitrate and acetyl-CoA to succinate, malate, and CoA. The increased longevity provided by malate addition did not occur in fumarase (fum-1), glyoxylate shunt (gei-7), succinate dehydrogenase flavoprotein (sdha-2), or soluble fumarate reductase F48E8.3 RNAi knockdown worms. Therefore, to increase lifespan, malate must be first converted to fumarate, then fumarate must be reduced to succinate by soluble fumarate reductase and the mitochondrial electron transport chain complex II. Reduction of fumarate to succinate is coupled with the oxidation of FADH2 to FAD. Lifespan extension induced by malate depended upon the longevity regulators DAF-16 and SIR-2.1. Malate supplementation did not extend the lifespan of long-lived eat-2 mutant worms, a model of dietary restriction. Malate and fumarate addition increased oxygen consumption, but decreased ATP levels and mitochondrial membrane potential suggesting a mild uncoupling of oxidative phosphorylation. Malate also increased NADPH, NAD, and the NAD/NADH ratio. Fumarate reduction, glyoxylate shunt activity, and mild mitochondrial uncoupling likely contribute to the lifespan extension induced by malate and fumarate by increasing the amount of oxidized NAD and FAD cofactors.
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