PDF(Pubmed)
Abstract：
In humans, a neomorphic isocitrate dehydrogenase mutation (idh-1neo) causes increased levels of cellular D-2-hydroxyglutarate (D-2HG), a proposed oncometabolite. However, the physiological effects of increased D-2HG and whether additional metabolic changes occur in the presence of an idh-1neo mutation are not well understood. We created a Caenorhabditis elegans model to study the effects of the idh-1neo mutation in a whole animal. Comparing the phenotypes exhibited by the idh-1neo to ∆dhgd-1 (D-2HG dehydrogenase) mutant animals, which also accumulate D-2HG, we identified a specific vitamin B12 diet-dependent vulnerability in idh-1neo mutant animals that leads to increased embryonic lethality. Through a genetic screen, we found that impairment of the glycine cleavage system, which generates one-carbon donor units, exacerbates this phenotype. In addition, supplementation with alternate sources of one-carbon donors suppresses the lethal phenotype. Our results indicate that the idh-1neo mutation imposes a heightened dependency on the one-carbon pool and provides a further understanding of how this oncogenic mutation rewires cellular metabolism.
摘要：
在人类中,新形异柠檬酸脱氢酶突变（idh-1neo）导致细胞D-2-羟基戊二酸（D-2HG）水平升高，一种拟议的碳代谢物。然而,D-2HG增加的生理效应以及在存在idh-1neo突变的情况下是否会发生额外的代谢变化尚不清楚.我们创建了一个秀丽隐杆线虫模型来研究idh-1neo突变对整个动物的影响。比较由idh-1neo表现出的表型Δdhgd-1（D-2HG脱氢酶）突变动物，也积累了D-2HG，我们在idh-1neo突变动物中发现了一种特定的维生素B12饮食依赖性脆弱性,该脆弱性导致胚胎致死率增加.通过基因筛选，我们发现甘氨酸裂解系统受损，产生一碳供体单位，加剧了这种表型。此外,补充其他来源的一碳供体会抑制致死表型。我们的结果表明，idh-1neo突变对单碳库的依赖性增强，并进一步了解了这种致癌突变如何重新连接细胞代谢。
