https://ror.org/0464eyp60 Department of Systems Biology, University of Massachusetts Chan Medical School, Worcester, MA, USA
https://ror.org/05fs6jp91 Department of Biochemistry and Molecular Biology, University of New Mexico School of Medicine, Albuquerque, NM, USA.
Life Sci Alliance. 2024 Jul 15;7(10). doi: 10.26508/lsa.202402924. Print 2024 Oct.
In humans, a neomorphic isocitrate dehydrogenase mutation () 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 mutation are not well understood. We created a model to study the effects of the mutation in a whole animal. Comparing the phenotypes exhibited by the to (D-2HG dehydrogenase) mutant animals, which also accumulate D-2HG, we identified a specific vitamin B12 diet-dependent vulnerability in 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 mutation imposes a heightened dependency on the one-carbon pool and provides a further understanding of how this oncogenic mutation rewires cellular metabolism.
在人类中，一种新形成的异柠檬酸脱氢酶突变 () 导致细胞 D-2-羟戊酸 (D-2HG) 水平升高，D-2HG 是一种被提议的致癌代谢物。然而，增加的 D-2HG 的生理影响以及在存在 突变的情况下是否会发生其他代谢变化尚不清楚。我们创建了一个 模型来研究 突变在整个动物中的影响。将 表现出的表型与也积累 D-2HG 的 (D-2-羟戊酸脱氢酶) 突变动物进行比较，我们发现 突变动物存在一种特定的维生素 B12 饮食依赖性脆弱性，导致胚胎致死率增加。通过遗传筛选，我们发现甘氨酸裂解系统的损伤会加剧这种表型，甘氨酸裂解系统产生一碳供体单位。此外，补充替代的一碳供体来源可以抑制致死表型。我们的结果表明， 突变使细胞对一碳池的依赖性增加，并进一步了解这种致癌突变如何重塑细胞代谢。
