{"doi":"10.1371/journal.pbio.3002057","title":"A D-2-hydroxyglutarate dehydrogenase mutant reveals a critical role for ketone body metabolism in Caenorhabditis elegans development","abstract":"In humans, mutations in D-2-hydroxyglutarate (D-2HG) dehydrogenase (D2HGDH) result in D-2HG accumulation, delayed development, seizures, and ataxia. While the mechanisms of 2HG-associated diseases have been studied extensively, the endogenous metabolism of D-2HG remains unclear in any organism. Here, we find that, in Caenorhabditis elegans, D-2HG is produced in the propionate shunt, which is transcriptionally activated when flux through the canonical, vitamin B12-dependent propionate breakdown pathway is perturbed. Loss of the D2HGDH ortholog, dhgd-1, results in embryonic lethality, mitochondrial defects, and the up-regulation of ketone body metabolism genes. Viability can be rescued by RNAi of hphd-1, which encodes the enzyme that produces D-2HG or by supplementing either vitamin B12 or the ketone bodies 3-hydroxybutyrate (3HB) and acetoacetate (AA). Altogether, our findings support a model in which C. elegans relies on ketone bodies for energy when vitamin B12 levels are low and in which a loss of dhgd-1 causes lethality by limiting ketone body production.","journal":"PLoS Biology","year":2023,"id":338267,"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":17,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.957,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2023-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":305727,"name":"Hefei Zhang","orcid":"0000-0002-5187-7166","position":1,"is_corresponding":false},{"id":305728,"name":"Xuhang Li","orcid":"0000-0001-6071-9605","position":2,"is_corresponding":false},{"id":352620,"name":"Shivani Nanda","orcid":"0000-0001-6358-2392","position":3,"is_corresponding":false},{"id":553239,"name":"Thomas B. Leland","orcid":null,"position":4,"is_corresponding":false},{"id":352621,"name":"Bennett W. Fox","orcid":"0000-0002-9749-3491","position":5,"is_corresponding":false},{"id":1071181,"name":"Alyxandra N. Starbard","orcid":null,"position":6,"is_corresponding":false},{"id":305725,"name":"Gabrielle E. Giese","orcid":"0000-0002-9338-2049","position":7,"is_corresponding":false},{"id":72618,"name":"Frank C. Schroeder","orcid":"0000-0002-4420-0237","position":8,"is_corresponding":false},{"id":352619,"name":"L. Şafak Yılmaz","orcid":"0000-0001-8258-4465","position":9,"is_corresponding":false},{"id":305730,"name":"Albertha J.M. Walhout","orcid":"0000-0001-5587-3608","position":10,"is_corresponding":false},{"id":305726,"name":"Olga Ponomarova","orcid":"0000-0001-6331-9949","position":0,"is_corresponding":true}],"reference_count":49,"raw_metadata":null,"created_at":"2026-07-19T01:10:35.973121Z","pmid":"37043428","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":[]}