{"doi":"10.1016/j.jlr.2022.100255","title":"Skin fibroblast metabolomic profiling reveals that lipid dysfunction predicts the severity of Friedreich’s ataxia","abstract":"Friedreich's ataxia (FRDA) is an autosomal recessive neurodegenerative disorder caused by a triplet guanine-adenine-adenine (GAA) repeat expansion in intron 1 of the FXN gene, which leads to decreased levels of the frataxin protein. Frataxin is involved in the formation of iron-sulfur (Fe-S) cluster prosthetic groups for various metabolic enzymes. To provide a better understanding of the metabolic status of patients with FRDA, here we used patient-derived fibroblast cells as a surrogate tissue for metabolic and lipidomic profiling by liquid chromatography-high resolution mass spectrometry. We found elevated HMG-CoA and β-hydroxybutyrate-CoA levels, implying dysregulated fatty acid oxidation, which was further demonstrated by elevated acyl-carnitine levels. Lipidomic profiling identified dysregulated levels of several lipid classes in FRDA fibroblast cells when compared with non-FRDA fibroblast cells. For example, levels of several ceramides were significantly increased in FRDA fibroblast cells; these results positively correlated with the GAA repeat length and negatively correlated with the frataxin protein levels. Furthermore, stable isotope tracing experiments indicated increased ceramide synthesis, especially for long-chain fatty acid-ceramides, in FRDA fibroblast cells compared with ceramide synthesis in healthy control fibroblast cells. In addition, PUFA-containing triglycerides and phosphatidylglycerols were enriched in FRDA fibroblast cells and negatively correlated with frataxin levels, suggesting lipid remodeling as a result of FXN deficiency. Altogether, we demonstrate patient-derived fibroblast cells exhibited dysregulated metabolic capabilities, and their lipid dysfunction predicted the severity of FRDA, making them a useful surrogate to study the metabolic status in FRDA.","journal":"Journal of Lipid Research","year":2022,"id":242610,"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":37,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9587,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2022-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":632099,"name":"Elaine S. Ho","orcid":"0000-0001-9111-7973","position":1,"is_corresponding":false},{"id":874370,"name":"M. Grazia Cotticelli","orcid":null,"position":2,"is_corresponding":false},{"id":421460,"name":"Peining Xu","orcid":null,"position":3,"is_corresponding":false},{"id":378326,"name":"Jill S. Napierala","orcid":"0000-0002-5141-0822","position":4,"is_corresponding":false},{"id":357466,"name":"Lauren Hauser","orcid":null,"position":5,"is_corresponding":false},{"id":379729,"name":"Marek Napierala","orcid":null,"position":6,"is_corresponding":false},{"id":15860,"name":"Blanca E. Himes","orcid":"0000-0002-2868-1333","position":7,"is_corresponding":false},{"id":873637,"name":"Robert B. Wilson","orcid":"0000-0001-6059-9762","position":8,"is_corresponding":false},{"id":356140,"name":"David R. Lynch","orcid":"0000-0001-7168-214X","position":9,"is_corresponding":false},{"id":500948,"name":"Clementina Mesaros","orcid":"0000-0001-5117-2038","position":10,"is_corresponding":false},{"id":278624,"name":"Dezhen Wang","orcid":"0000-0003-3984-6946","position":0,"is_corresponding":true}],"reference_count":67,"raw_metadata":null,"created_at":"2026-07-19T00:23:10.218426Z","pmid":"35850241","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":[]}