{"doi":"10.1093/g3journal/jkaf132","title":"New alleles of D-2-hydroxyglutarate dehydrogenase enable studies of oncometabolite function in <i>Drosophila melanogaster</i>","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.","journal":"G3 Genes Genomes Genetics","year":2025,"id":567796,"datarank":0.0,"base_score":0.0,"endowment":0.0,"self_citation_contribution":0.0,"citation_network_contribution":0.0,"self_endowment_contribution":0.0,"citer_contribution":0.0,"corpus_percentile":null,"corpus_rank":null,"citation_count":0,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9588,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2025-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":1472354,"name":"Prince Okah","orcid":null,"position":1,"is_corresponding":false},{"id":941952,"name":"Shefali A. Shefali","orcid":"0000-0001-8334-5351","position":2,"is_corresponding":false},{"id":379043,"name":"Alexander J. Fitt","orcid":"0000-0001-9002-8346","position":3,"is_corresponding":false},{"id":1472355,"name":"Miaozhong Shen","orcid":null,"position":4,"is_corresponding":false},{"id":436930,"name":"Mandkhai Molomjamts","orcid":null,"position":5,"is_corresponding":false},{"id":587941,"name":"Robert Pepin","orcid":"0000-0002-1828-1598","position":6,"is_corresponding":false},{"id":110269,"name":"Travis Nemkov","orcid":"0000-0001-8566-7119","position":7,"is_corresponding":false},{"id":28360,"name":"Angelo D’Alessandro","orcid":"0000-0002-2258-6490","position":8,"is_corresponding":false},{"id":376332,"name":"Jason M. Tennessen","orcid":"0000-0002-3527-5683","position":9,"is_corresponding":false},{"id":941951,"name":"Madhulika Rai","orcid":"0000-0003-0228-285X","position":0,"is_corresponding":true}],"reference_count":38,"raw_metadata":null,"created_at":"2026-07-19T02:56:48.183032Z","pmid":"40489577","pmcid":null,"fwci":null,"citation_percentile":null,"influential_citations":0,"oa_status":null,"license":null,"views":0,"total_file_size_bytes":0,"version_count":0,"fair_f":null,"fair_a":null,"fair_i":null,"fair_r":null,"fair_zscore":null,"fair_rationale":null,"fair_model":null,"fair_agent_version":null,"fair_fulltext_source":null,"fair_has_llm":null,"fair_computed_at":null,"clinical_trials":[],"software_tools":[],"db_accessions":[],"linked_datasets":[],"topics":[]}