# New alleles of D-2-hydroxyglutarate dehydrogenase enable studies of oncometabolite function in Drosophila melanogaster

## TL;DR

Researchers created new fruit fly mutants to study how the oncometabolite D-2HG affects development and metabolism.

## Contribution

The paper introduces two novel D2hgdh loss-of-function alleles in Drosophila for studying D-2HG function.

## Key findings

- The D2hgdh mutants show elevated D-2HG levels and distinct developmental and metabolomic phenotypes.
- The new alleles provide a model to study context-dependent effects of D-2HG in human disease and normal physiology.

## Abstract

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.

Aberrant accumulation of the metabolite D-2-hydroxyglutarate (D-2HG) is implicated in cancer progression and neurometabolic disorders, though its pathological effects vary depending on genetic context. To explore how genetic background influences D-2HG-associated phenotypes, Rai et al. generated two loss-of-function alleles in the Drosophila melanogaster gene D2hgdh, which encodes the enzyme responsible for degrading D-2HG. These mutants exhibit elevated D-2HG levels along with distinct developmental and metabolic abnormalities. Overall, the authors’ 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.