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Research Paper Non-linear impact of glutathione depletion on C. elegans life span and stress resistance

机译：谷胱甘肽耗竭对秀丽隐杆线虫寿命和抗逆性的非线性影响

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The redox environment in cells and organisms is set by low-molecular mass and protein-bound thiols, with glutathione (GSH) representing a major intracellular redox buffer. Subtle thiol oxidation elicits signal transduction processes and adaptive responses to cope with stressors, whereas highly oxidizing conditions may provoke cell death. We here tested how thiol depletion affects life span, stress resistance and stress signaling in the model organism Caenorhabditis elegans . Diethyl maleate (DEM), an α,β-unsaturated carbonyl compound that conjugates to GSH and other thiols, decreased C. elegans life span at a concentration of 1 mM. In contrast, low and moderate doses of DEM (10–100 μM) increased mean and maximum life span and improved resistance against oxidative stress. DEM-induced life span extension was not detectable in worms deficient in either the FoxO orthologue, DAF-16, or the Nrf2 orthologue, SKN-1, pointing to a collaborative role of the two transcription factors in life span extension induced by thiol depletion. Cytoprotective target genes of DAF-16 and SKN-1 were upregulated after at least 3 days of exposure to 100 μM DEM, but not 1 mM DEM, whereas only 1 mM DEM caused upregulation of egl-1 , a gene controlled by a p53-orthologue, CEP-1. In order to test whether depletion of GSH may elicit effects similar to DEM, we suppressed GSH biosynthesis in worms by attenuating γ-glutamylcysteine synthetase ( gcs-1 ) expression through RNAi. The decline in GSH levels elicited by gcs-1 knockdown starting at young adult stage did not impair viability, but increased both stress resistance and life expectancy of the worms. In contrast, gcs-1 knockdown commencing right after hatching impaired nematode stress resistance and rendered young adult worms prone to vulval ruptures during egg-laying. Thus, modest decrease in GSH levels in young adult worms may promote stress resistance and life span, whereas depletion of GSH is detrimental to freshly hatched and developing worms.
机译：细胞和生物体中的氧化还原环境由低分子质量和与蛋白质结合的硫醇决定，其中谷胱甘肽（GSH）代表主要的细胞内氧化还原缓冲液。微妙的硫醇氧化引发信号转导过程和适应性应激应对应激，而高度氧化的条件可能会导致细胞死亡。在这里，我们测试了模型生物秀丽隐杆线虫（Caenorhabditis elegans）中硫醇的消耗如何影响寿命，抗逆性和应力信号传递。马来酸二乙酯（DEM）是一种与GSH和其他硫醇结合的α，β-不饱和羰基化合物，在浓度为1 mM时，线虫的寿命缩短。相比之下，低和中等剂量的DEM（10-100μM）会增加平均寿命和最大寿命，并提高对氧化应激的抵抗力。在缺乏FoxO直向同源物DAF-16或Nrf2直向同源物SKN-1的蠕虫中，无法检测到DEM诱导的寿命延长，这表明两种转录因子在硫醇耗尽诱导的寿命延长中具有协同作用。暴露于100μMDEM至少3天后，DAF-16和SKN-1的细胞保护靶基因被上调，但未暴露于1 mM DEM，而只有1 mM DEM引起egl-1的上调，egl-1是由p53-直向同源物，CEP-1。为了测试GSH的耗竭是否会引起类似于DEM的作用，我们通过通过RNAi减弱γ-谷氨酰半胱氨酸合成酶（gcs-1）的表达来抑制蠕虫中GSH的生物合成。从年轻的成年阶段开始，由gcs-1敲低引起的GSH含量下降并未损害其生存能力，但增加了蠕虫的抗逆性和预期寿命。相反，孵化后立即开始的gcs-1敲低削弱了线虫的抗压力能力，并使年轻的成年蠕虫在产卵过程中容易发生外阴破裂。因此，成年幼虫中GSH含量的适度下降可能会促进抗逆性和寿命，而GSH的消耗对刚孵化和发育的蠕虫有害。

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