{"doi":"10.1242/dmm.045898","title":"Teleological role of L-2-hydroxyglutarate dehydrogenase in the kidney","abstract":"ABSTRACT L-2-hydroxyglutarate (L-2HG) is an oncometabolite found elevated in renal tumors. However, this molecule might have physiological roles that extend beyond its association with cancer, as L-2HG levels are elevated in response to hypoxia and during Drosophila larval development. L-2HG is known to be metabolized by L-2HG dehydrogenase (L2HGDH), and loss of L2HGDH leads to elevated L-2HG levels. Despite L2HGDH being highly expressed in the kidney, its role in renal metabolism has not been explored. Here, we report our findings utilizing a novel CRISPR/Cas9 murine knockout model, with a specific focus on the role of L2HGDH in the kidney. Histologically, L2hgdh knockout kidneys have no demonstrable histologic abnormalities. However, GC-MS metabolomics demonstrates significantly reduced levels of the TCA cycle intermediate succinate in multiple tissues. Isotope labeling studies with [U-13C] glucose demonstrate that restoration of L2HGDH in renal cancer cells (which lowers L-2HG) leads to enhanced incorporation of label into TCA cycle intermediates. Subsequent biochemical studies demonstrate that L-2HG can inhibit the TCA cycle enzyme α-ketoglutarate dehydrogenase. Bioinformatic analysis of mRNA expression data from renal tumors demonstrates that L2HGDH is co-expressed with genes encoding TCA cycle enzymes as well as the gene encoding the transcription factor PGC-1α, which is known to regulate mitochondrial metabolism. Restoration of PGC-1α in renal tumor cells results in increased L2HGDH expression with a concomitant reduction in L-2HG levels. Collectively, our analyses provide new insight into the physiological role of L2HGDH as well as mechanisms that promote L-2HG accumulation in disease states.","journal":"Disease Models & Mechanisms","year":2020,"id":71159,"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":18,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9512,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2020-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":356398,"name":"Hyeyoung Nam","orcid":"0000-0002-9964-728X","position":1,"is_corresponding":false},{"id":376331,"name":"Eun‐Hee Shim","orcid":"0000-0002-5151-3901","position":2,"is_corresponding":false},{"id":356404,"name":"Richard Kirkman","orcid":"0000-0002-4212-0751","position":3,"is_corresponding":false},{"id":356397,"name":"Anirban Kundu","orcid":"0000-0003-0621-9989","position":4,"is_corresponding":false},{"id":356401,"name":"Suman Karki","orcid":"0000-0003-4393-4041","position":5,"is_corresponding":false},{"id":377643,"name":"Yasaman Heidarian","orcid":null,"position":6,"is_corresponding":false},{"id":376332,"name":"Jason M. Tennessen","orcid":"0000-0002-3527-5683","position":7,"is_corresponding":false},{"id":376333,"name":"Juan Liu","orcid":"0009-0001-2278-5553","position":8,"is_corresponding":false},{"id":88693,"name":"Jason W. Locasale","orcid":"0000-0002-7766-3502","position":9,"is_corresponding":false},{"id":376334,"name":"Tao Guo","orcid":"0000-0002-6898-9797","position":10,"is_corresponding":false},{"id":242397,"name":"Shi Wei","orcid":"0000-0003-4417-593X","position":11,"is_corresponding":false},{"id":289539,"name":"Jennifer Gordetsky","orcid":"0000-0002-0745-2160","position":12,"is_corresponding":false},{"id":368482,"name":"Teresa L. Johnson‐Pais","orcid":"0000-0001-7580-1206","position":13,"is_corresponding":false},{"id":1823,"name":"Devin Absher","orcid":"0000-0003-4405-1646","position":14,"is_corresponding":false},{"id":376335,"name":"Dinesh Rakheja","orcid":"0000-0001-6888-7902","position":15,"is_corresponding":false},{"id":376336,"name":"Anil K. Challa","orcid":"0000-0002-3633-3304","position":16,"is_corresponding":false},{"id":356407,"name":"Sunil Sudarshan","orcid":"0000-0001-7257-6277","position":17,"is_corresponding":false},{"id":356400,"name":"Garrett J. Brinkley","orcid":"0000-0003-2622-3416","position":0,"is_corresponding":true}],"reference_count":64,"raw_metadata":null,"created_at":"2026-07-18T21:43:57.004133Z","pmid":"32928875","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":[]}