{"doi":"10.1172/jci.insight.156346","title":"Dichloroacetate improves mitochondrial function, physiology, and morphology in FBXL4 disease models","abstract":"Pathogenic variants in the human F-box and leucine-rich repeat protein 4 (FBXL4) gene result in an autosomal recessive, multisystemic, mitochondrial disorder involving variable mitochondrial depletion and respiratory chain complex deficiencies with lactic acidemia. As no FDA-approved effective therapies for this disease exist, we sought to characterize translational C. elegans and zebrafish animal models, as well as human fibroblasts, to study FBXL4-/- disease mechanisms and identify preclinical therapeutic leads. Developmental delay, impaired fecundity and neurologic and/or muscular activity, mitochondrial dysfunction, and altered lactate metabolism were identified in fbxl-1(ok3741) C. elegans. Detailed studies of a PDHc activator, dichloroacetate (DCA), in fbxl-1(ok3741) C. elegans demonstrated its beneficial effects on fecundity, neuromotor activity, and mitochondrial function. Validation studies were performed in fbxl4sa12470 zebrafish larvae and in FBXL4-/- human fibroblasts; they showed DCA efficacy in preventing brain death, impairment of neurologic and/or muscular function, mitochondrial biochemical dysfunction, and stress-induced morphologic and ultrastructural mitochondrial defects. These data demonstrate that fbxl-1(ok3741) C. elegans and fbxl4sa12470 zebrafish provide robust translational models to study mechanisms and identify preclinical therapeutic candidates for FBXL4-/- disease. Furthermore, DCA is a lead therapeutic candidate with therapeutic benefit on diverse aspects of survival, neurologic and/or muscular function, and mitochondrial physiology that warrants rigorous clinical trial study in humans with FBXL4-/- disease.","journal":"JCI Insight","year":2022,"id":270291,"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":14,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9426,"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":720721,"name":"Eiko Nakamaru‐Ogiso","orcid":"0000-0003-0931-1940","position":1,"is_corresponding":false},{"id":720717,"name":"Neal D. Mathew","orcid":"0000-0002-4681-9228","position":2,"is_corresponding":false},{"id":934062,"name":"Elizabeth T. Herman","orcid":"0000-0003-3719-7479","position":3,"is_corresponding":false},{"id":356530,"name":"Nina Shah","orcid":"0000-0002-1971-8173","position":4,"is_corresponding":false},{"id":402292,"name":"Suraiya Haroon","orcid":"0000-0001-5575-4609","position":5,"is_corresponding":false},{"id":287815,"name":"Rui Xiao","orcid":"0000-0002-2727-8171","position":6,"is_corresponding":false},{"id":720719,"name":"Christoph Seiler","orcid":"0000-0002-3917-1689","position":7,"is_corresponding":false},{"id":249295,"name":"Marni J. Falk","orcid":"0000-0002-1723-6728","position":8,"is_corresponding":false},{"id":898192,"name":"Manuela Lavorato","orcid":"0000-0001-6170-259X","position":0,"is_corresponding":true}],"reference_count":74,"raw_metadata":null,"created_at":"2026-07-19T00:27:26.772098Z","pmid":"35881484","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":[]}