Rai Madhulika, Okah Prince, Shefali Shefali A, Fitt Alexander J, Shen Michael Z, Molomjamts Mandkhai, Pepin Robert, Nemkov Travis, D'Alessandro Angelo, Tennessen Jason M
Department of Biology, Indiana University, Bloomington, IN 47405, USA.
Department of Chemistry, Indiana University, Bloomington, IN 47405, USA.
G3 (Bethesda). 2025 Aug 6;15(8). doi: 10.1093/g3journal/jkaf132.
D-2-hydroxyglutarate (D-2HG) is a potent oncometabolite capable of disrupting chromatin architecture, altering metabolism, and promoting cellular dedifferentiation. As a result, ectopic D-2HG accumulation induces neurometabolic disorders and promotes progression of multiple cancers. However, the disease-associated effects of ectopic D-2HG accumulation are dependent on genetic context. Specifically, neomorphic mutations in the mammalian genes Isocitrate dehydrogenase 1 (IDH1) and IDH2 result in the production of enzymes that inappropriately generate D-2HG from α-ketoglutarate (αKG). Within this genetic background, D-2HG acts as an oncometabolite and is associated with multiple cancers, including several diffuse gliomas. In contrast, loss-of-function mutations in the gene D-2-hydroxyglutarate dehydrogenase (D2hgdh) render cells unable to degrade D-2HG, resulting in excessive buildup of this molecule. D2hgdh mutations, however, are not generally associated with elevated cancer risk. This discrepancy raises the question as to why ectopic D-2HG accumulation in humans induces context-dependent disease outcomes. To enable such genetic studies in vivo, we generated 2 novel loss-of-function mutations in the Drosophila melanogaster gene D2hgdh and validated that these alleles result in ectopic D-2HG. Moreover, we observed that D2hgdh mutations induce developmental and metabolomic phenotypes indicative of elevated D-2HG accumulation. Overall, our efforts provide the Drosophila community with new mutant strains that can be used to study D-2HG function in human disease models as well as in the context of normal growth, metabolism, and physiology.
D-2-羟基戊二酸（D-2HG）是一种强效的致癌代谢物，能够破坏染色质结构、改变代谢并促进细胞去分化。因此，异位D-2HG积累会诱发神经代谢紊乱并促进多种癌症的进展。然而，异位D-2HG积累所产生的与疾病相关的影响取决于遗传背景。具体而言，哺乳动物异柠檬酸脱氢酶1（IDH1）和IDH2基因中的新形态突变会导致产生从α-酮戊二酸（αKG）不适当生成D-2HG的酶。在这种遗传背景下，D-2HG作为一种致癌代谢物，与多种癌症相关，包括几种弥漫性胶质瘤。相比之下，D-2-羟基戊二酸脱氢酶（D2hgdh）基因的功能丧失突变使细胞无法降解D-2HG，导致该分子过度积累。然而，D2hgdh突变通常与癌症风险升高无关。这种差异引发了一个问题，即为什么人类体内异位D-2HG积累会导致依赖于背景的疾病结果。为了在体内进行此类遗传研究，我们在果蝇基因D2hgdh中产生了2种新的功能丧失突变，并验证了这些等位基因会导致异位D-2HG。此外，我们观察到D2hgdh突变会诱导发育和代谢组学表型，表明D-2HG积累增加。总体而言，我们的工作为果蝇研究群体提供了新的突变株，可用于在人类疾病模型以及正常生长、代谢和生理背景下研究D-2HG的功能。
