{"doi":"10.1101/2025.09.29.679238","title":"Itaconate is metabolized to 2-hydroxymethylsuccinate through a CoA-independent degradation pathway in mitochondria","abstract":"Abstract The immunometabolite itaconate modulates cellular metabolism and is converted into structurally similar C 5 dicarboxylates that require advanced analytics to decipher their metabolic fate. Here, we employ high-resolution mass spectrometry and tracing approaches and identify 2-hydroxymethylsuccinate (2HMS) as a previously unrecognized C 5 dicarboxylate derived from itaconate. 2HMS synthesis occurs during inflammatory responses and upon itaconate treatment, as detected by 13 C itaconate tracing. Pathway analysis reveals that methylglutaconyl-CoA hydratase (AUH) drives 2HMS synthesis through a CoA-independent conversion (CIC) pathway. This pathway is distinct from the CoA-dependent conversion (CDC) pathway that generates mesaconate and itaconyl-CoA influencing B 12 -dependent processes. In vivo inflammation studies reveal that adipose tissue prefers CIC to produce 2HMS and liver favors CDC-mediated mesaconate synthesis, highlighting tissue-specific itaconate degradation routes. This study identifies a new branch of itaconate metabolism, provides an analytical framework to resolve C 5 dicarboxylate networks, and links 2HMS to inflammation and mitochondrial metabolism that might be targeted therapeutically.","journal":"bioRxiv (Cold Spring Harbor Laboratory)","year":2025,"id":576335,"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":0.9532,"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":1485255,"name":"Laura Hadam","orcid":null,"position":1,"is_corresponding":false},{"id":1374041,"name":"Birte Dowerg","orcid":null,"position":2,"is_corresponding":false},{"id":1484847,"name":"Vadim S. Korotkov","orcid":"0000-0003-3970-2483","position":3,"is_corresponding":false},{"id":631025,"name":"Connor S.R. Jankowski","orcid":"0000-0003-1247-4548","position":4,"is_corresponding":false},{"id":1485256,"name":"Ulrike Beutling","orcid":null,"position":5,"is_corresponding":false},{"id":1374040,"name":"Hanna F Willenbockel","orcid":null,"position":6,"is_corresponding":false},{"id":1485257,"name":"Ulrike Brandt","orcid":null,"position":7,"is_corresponding":false},{"id":848205,"name":"Eva Medina","orcid":"0000-0002-5935-3260","position":8,"is_corresponding":false},{"id":1484848,"name":"André Fleißner","orcid":"0000-0001-5841-3199","position":9,"is_corresponding":false},{"id":1485258,"name":"Henrikus Garritsen","orcid":null,"position":10,"is_corresponding":false},{"id":1484849,"name":"Michael Jarek","orcid":"0000-0001-7751-9458","position":11,"is_corresponding":false},{"id":91599,"name":"Raimo Franke","orcid":"0000-0002-5407-5521","position":12,"is_corresponding":false},{"id":1098871,"name":"Thomas Weichhart","orcid":"0000-0002-4349-0797","position":13,"is_corresponding":false},{"id":703168,"name":"Mark Brönstrup","orcid":"0000-0002-8971-7045","position":14,"is_corresponding":false},{"id":1484850,"name":"Meina Neumann‐Schaal","orcid":"0000-0002-1641-019X","position":15,"is_corresponding":false},{"id":233744,"name":"Thekla Cordes","orcid":"0000-0002-8097-191X","position":16,"is_corresponding":false},{"id":317854,"name":"Fangfang Chen","orcid":"0000-0001-7396-4052","position":0,"is_corresponding":true}],"reference_count":66,"raw_metadata":{"citation_network_status":"fetched"},"created_at":"2026-07-19T02:57:56.636458Z","pmid":null,"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":[]}