{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,8]],"date-time":"2026-10-08T07:49:47Z","timestamp":1791445787267,"version":"4.3.3"},"reference-count":47,"publisher":"Wiley","issue":"6","license":[{"start":{"date-parts":[[2026,10,7]],"date-time":"2026-10-07T00:00:00Z","timestamp":1791331200000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"},{"start":{"date-parts":[[2026,10,7]],"date-time":"2026-10-07T00:00:00Z","timestamp":1791331200000},"content-version":"tdm","delay-in-days":0,"URL":"http:\/\/doi.wiley.com\/10.1002\/tdm_license_1.1"}],"funder":[{"DOI":"10.13039\/100000002","name":"National Institutes of Health","doi-asserted-by":"publisher","award":["R35\u2010GM134863"],"award-info":[{"award-number":["R35\u2010GM134863"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["J of Inher Metab Disea"],"published-print":{"date-parts":[[2026,11]]},"abstract":"<jats:title>ABSTRACT<\/jats:title>\n                  <jats:p>\n                    Pyruvate dehydrogenase complex (PDHc) deficiency (PDCD) is a primary mitochondrial disorder characterized by neurodevelopmental disability, altered intermediary metabolism, and early mortality. Dichloroacetate (DCA), a pyruvate analog, activates PDHc and remains under clinical investigation for treatment of PDCD. Here, we studied the in\u00a0vivo efficacy of a five\u2010point log concentration range of DCA on animal health and metabolism in\n                    <jats:styled-content style=\"fixed-case\">\n                      <jats:italic>C. elegans<\/jats:italic>\n                    <\/jats:styled-content>\n                    with feeding RNA interference (RNAi) expression knockdown of either\n                    <jats:italic>PDHA\u20101<\/jats:italic>\n                    or\n                    <jats:italic>DLD\u20101<\/jats:italic>\n                    homologs at graded degrees to model variable disease severity. These worm models recapitulate phenotypic features of PDCD observed in human patients, including reduced survival, delayed growth, locomotor impairment, and elevated lactate and\/or pyruvate tissue levels. DCA treatment appeared well\u2010tolerated, with no gross morphologic toxicity seen at doses up to 25\u2009mM. Significantly improved health, survival, tissue lactate levels, and mitochondrial physiology were observed at 25\u2009mM in\n                    <jats:italic>pdha\u20101(RNAi)<\/jats:italic>\n                    knockdown animals. DCA treatment in\n                    <jats:italic>dld\u20101(RNAi)<\/jats:italic>\n                    <jats:styled-content style=\"fixed-case\">\n                      <jats:italic>C. elegans<\/jats:italic>\n                    <\/jats:styled-content>\n                    models (undiluted, 1:20 dilution, and 1:100 dilution) significantly improved survival, neuromuscular function, and metabolic phenotypes primarily in the moderate (1:20) and\/or mild (1:100)\n                    <jats:italic>dld\u20101(RNAi)<\/jats:italic>\n                    deficiency strains, but not in full\u2010dose\n                    <jats:italic>dld\u20101(RNAi)<\/jats:italic>\n                    . Importantly, linear growth, neuromuscular activity, and mitochondrial physiology were significantly improved with DCA treatment even in the most severe\n                    <jats:italic>dld\u20101(RNAi)<\/jats:italic>\n                    undiluted model. Overall, preclinical modeling provides objective evidence of DCA therapeutic efficacy in\n                    <jats:styled-content style=\"fixed-case\">\n                      <jats:italic>C. elegans<\/jats:italic>\n                    <\/jats:styled-content>\n                    knockdown strains for two well\u2010conserved homologs of\n                    <jats:italic>PDHA1<\/jats:italic>\n                    and\n                    <jats:italic>DLD<\/jats:italic>\n                    representing distinct genetic etiologies of PDCD, with demonstrated beneficial effects on survival, healthspan, tissue lactate, and mitochondrial physiology. These data further confirm that DCA's therapeutic effect correlates with PDHc disease phenotype severity in\n                    <jats:italic>dld\u20101(RNAi)<\/jats:italic>\n                    animals.\n                  <\/jats:p>","DOI":"10.1002\/jimd.70257","type":"journal-article","created":{"date-parts":[[2026,10,8]],"date-time":"2026-10-08T06:51:31Z","timestamp":1791442291000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Dichloroacetate Improves Animal Survival, Growth, Neuromuscular Activity, Mitochondrial Stress and Physiology, and Elevated Lactate in\n                    <scp>\n                      <i>C. elegans<\/i>\n                    <\/scp>\n                    <i>pdha\u20101<\/i>\n                    and\n                    <i>dld\u20101<\/i>\n                    <scp>RNAi<\/scp>\n                    Models of Pyruvate Dehydrogenase Complex Deficiency (\n                    <scp>PDCD<\/scp>\n                    )"],"prefix":"10.1002","volume":"49","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-1062-3071","authenticated-orcid":false,"given":"Cristina","family":"Remes","sequence":"first","affiliation":[{"name":"Mitochondrial Medicine Frontier Program, Division of Genetic and Genomic Medicine, Department of Pediatrics The Children's Hospital of Philadelphia (CHOP)  Philadelphia Pennsylvania USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Neal D.","family":"Mathew","sequence":"additional","affiliation":[{"name":"Mitochondrial Medicine Frontier Program, Division of Genetic and Genomic Medicine, Department of Pediatrics The Children's Hospital of Philadelphia (CHOP)  Philadelphia Pennsylvania USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0003-1741-9174","authenticated-orcid":false,"given":"Victoria","family":"Miranda","sequence":"additional","affiliation":[{"name":"Mitochondrial Medicine Frontier Program, Division of Genetic and Genomic Medicine, Department of Pediatrics The Children's Hospital of Philadelphia (CHOP)  Philadelphia Pennsylvania USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Suraiya","family":"Haroon","sequence":"additional","affiliation":[{"name":"Mitochondrial Medicine Frontier Program, Division of Genetic and Genomic Medicine, Department of Pediatrics The Children's Hospital of Philadelphia (CHOP)  Philadelphia Pennsylvania USA"},{"name":"Department of Pediatrics Perelman School of Medicine, University of Pennsylvania  Philadelphia Pennsylvania USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tyler","family":"O'Hara","sequence":"additional","affiliation":[{"name":"Mitochondrial Medicine Frontier Program, Division of Genetic and Genomic Medicine, Department of Pediatrics The Children's Hospital of Philadelphia (CHOP)  Philadelphia Pennsylvania USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1699-7621","authenticated-orcid":false,"given":"Vernon E.","family":"Anderson","sequence":"additional","affiliation":[{"name":"Mitochondrial Medicine Frontier Program, Division of Genetic and Genomic Medicine, Department of Pediatrics The Children's Hospital of Philadelphia (CHOP)  Philadelphia Pennsylvania USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Manuela","family":"Lavorato","sequence":"additional","affiliation":[{"name":"Mitochondrial Medicine Frontier Program, Division of Genetic and Genomic Medicine, Department of Pediatrics The Children's Hospital of Philadelphia (CHOP)  Philadelphia Pennsylvania USA"},{"name":"Department of Pediatrics Perelman School of Medicine, University of Pennsylvania  Philadelphia Pennsylvania USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7451-5117","authenticated-orcid":false,"given":"Kelsey","family":"Keith","sequence":"additional","affiliation":[{"name":"Department of Biomedical and Health Informatics The Children's Hospital of Philadelphia  Philadelphia Pennsylvania USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rui","family":"Xiao","sequence":"additional","affiliation":[{"name":"Department of Biostatistics, Perelman School of Medicine University of Pennsylvania  Philadelphia Pennsylvania USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Eiko","family":"Nakamaru\u2010Ogiso","sequence":"additional","affiliation":[{"name":"Mitochondrial Medicine Frontier Program, Division of Genetic and Genomic Medicine, Department of Pediatrics The Children's Hospital of Philadelphia (CHOP)  Philadelphia Pennsylvania USA"},{"name":"Department of Pediatrics Perelman School of Medicine, University of Pennsylvania  Philadelphia Pennsylvania USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Marni J.","family":"Falk","sequence":"additional","affiliation":[{"name":"Mitochondrial Medicine Frontier Program, Division of Genetic and Genomic Medicine, Department of Pediatrics The Children's Hospital of Philadelphia (CHOP)  Philadelphia Pennsylvania USA"},{"name":"Department of Pediatrics Perelman School of Medicine, University of Pennsylvania  Philadelphia Pennsylvania USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2026,10,7]]},"reference":[{"key":"e_1_2_12_2_1","doi-asserted-by":"publisher","DOI":"10.1002\/jimd.12463"},{"key":"e_1_2_12_3_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.ymgme.2012.03.017"},{"key":"e_1_2_12_4_1","doi-asserted-by":"publisher","DOI":"10.1007\/s10545\u2010016\u20100011\u20105"},{"key":"e_1_2_12_5_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.ymgme.2012.09.001"},{"key":"e_1_2_12_6_1","doi-asserted-by":"publisher","DOI":"10.1007\/s00247\u2010016\u20103585\u2010z"},{"key":"e_1_2_12_7_1","doi-asserted-by":"publisher","DOI":"10.1093\/jnen\/nlv022"},{"key":"e_1_2_12_8_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.str.2007.10.024"},{"key":"e_1_2_12_9_1","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.011597698"},{"key":"e_1_2_12_10_1","doi-asserted-by":"publisher","DOI":"10.1186\/s13023\u2010020\u201001586\u20103"},{"key":"e_1_2_12_11_1","doi-asserted-by":"publisher","DOI":"10.1007\/s42977\u2010023\u201000155\u20106"},{"key":"e_1_2_12_12_1","doi-asserted-by":"publisher","DOI":"10.1172\/jci.insight.156222"},{"key":"e_1_2_12_13_1","doi-asserted-by":"publisher","DOI":"10.1172\/jci.insight.178973"},{"key":"e_1_2_12_14_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.mito.2006.04.001"},{"key":"e_1_2_12_15_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.ymgme.2013.03.019"},{"key":"e_1_2_12_16_1","doi-asserted-by":"publisher","DOI":"10.1212\/wnl.53.3.612"},{"key":"e_1_2_12_17_1","doi-asserted-by":"publisher","DOI":"10.1007\/s00439\u2010009\u20100629\u20106"},{"key":"e_1_2_12_18_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.ymgme.2007.10.135"},{"key":"e_1_2_12_19_1","doi-asserted-by":"publisher","DOI":"10.1210\/jc.2005\u20100123"},{"key":"e_1_2_12_20_1","doi-asserted-by":"publisher","DOI":"10.1016\/0026\u20100495(89)90051\u20106"},{"key":"e_1_2_12_21_1","doi-asserted-by":"publisher","DOI":"10.1289\/ehp.98106s4989"},{"key":"e_1_2_12_22_1","doi-asserted-by":"publisher","DOI":"10.1203\/01.PDR.0000057987.46622.64"},{"key":"e_1_2_12_23_1","unstructured":"Saol Therapeutics Inc \u201cTrial of Dichloroacetate in Pyruvate Dehydrogenase Complex Deficiency: (DCA\/PDCD) \u201d2025 https:\/\/clinicaltrials.gov\/study\/NCT02616484?term=dichloroacetate&rank=1."},{"key":"e_1_2_12_24_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.ymgme.2013.12.011"},{"key":"e_1_2_12_25_1","unstructured":"R.Sapkota R.Harsha Cheppally A.Sharda andM.Karkee \u201cYOLO26: Key Architectural Enhancements and Performance Benchmarking for Real\u2010Time Object Detection \u201d2025 arXiv:2509.25164 https:\/\/doi.org\/10.48550\/arXiv.2509.25164."},{"key":"e_1_2_12_26_1","unstructured":"G.JocherandJ.Qiu 2023 https:\/\/github.com\/ultralytics\/ultralytics."},{"key":"e_1_2_12_27_1","doi-asserted-by":"crossref","unstructured":"M.Sandler A.Howard M.Zhu A.Zhmoginov andL.\u2010C.Chen \u201cMobileNetV2: Inverted Residuals and Linear Bottlenecks \u201d2018 arXiv:1801.04381 https:\/\/doi.org\/10.48550\/arXiv.1801.04381.","DOI":"10.1109\/CVPR.2018.00474"},{"key":"e_1_2_12_28_1","unstructured":"N. D.Mathew \u201cWormScan ML: Automated Alive\/Dead Lifespan Analysis ofC. elegans \u201d2026."},{"key":"e_1_2_12_29_1","doi-asserted-by":"publisher","DOI":"10.1101\/2021.10.18.464905"},{"key":"e_1_2_12_30_1","unstructured":"R Core Team \u201cA Language and Environment for Statistical Computing \u201d2006."},{"key":"e_1_2_12_31_1","doi-asserted-by":"publisher","DOI":"10.3791\/52321"},{"key":"e_1_2_12_32_1","doi-asserted-by":"publisher","DOI":"10.1101\/2024.10.27.620333"},{"key":"e_1_2_12_33_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.celrep.2018.02.099"},{"key":"e_1_2_12_34_1","doi-asserted-by":"publisher","DOI":"10.1172\/jci.insight.156346"},{"key":"e_1_2_12_35_1","doi-asserted-by":"publisher","DOI":"10.1038\/nmeth.2089"},{"key":"e_1_2_12_36_1","doi-asserted-by":"publisher","DOI":"10.1002\/jemt.20829"},{"key":"e_1_2_12_37_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41514\u2010017\u20100002\u20102"},{"key":"e_1_2_12_38_1","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0095265"},{"key":"e_1_2_12_39_1","doi-asserted-by":"publisher","DOI":"10.1152\/ajpendo.00457.2019"},{"key":"e_1_2_12_40_1","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0033483"},{"key":"e_1_2_12_41_1","doi-asserted-by":"publisher","DOI":"10.1038\/nature12188"},{"key":"e_1_2_12_42_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.cell.2010.12.016"},{"key":"e_1_2_12_43_1","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pgen.1002760"},{"key":"e_1_2_12_44_1","doi-asserted-by":"publisher","DOI":"10.1242\/jcs.01275"},{"key":"e_1_2_12_45_1","doi-asserted-by":"publisher","DOI":"10.1007\/978\u20101\u20100716\u20101732\u20108_16"},{"key":"e_1_2_12_46_1","doi-asserted-by":"publisher","DOI":"10.1111\/acel.12029"},{"key":"e_1_2_12_47_1","volume-title":"GeneReviews [Internet]","author":"Ganetzky R.","year":"2021"},{"key":"e_1_2_12_48_1","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pbio.0050259"}],"container-title":["Journal of Inherited Metabolic Disease"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/pdf\/10.1002\/jimd.70257","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/full-xml\/10.1002\/jimd.70257","content-type":"application\/xml","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/pdf\/10.1002\/jimd.70257","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,10,8]],"date-time":"2026-10-08T06:51:34Z","timestamp":1791442294000},"score":1,"resource":{"primary":{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/10.1002\/jimd.70257"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,10,7]]},"references-count":47,"journal-issue":{"issue":"6","published-print":{"date-parts":[[2026,11]]}},"alternative-id":["10.1002\/jimd.70257"],"URL":"https:\/\/doi.org\/10.1002\/jimd.70257","archive":["Portico"],"relation":{},"ISSN":["0141-8955","1573-2665"],"issn-type":[{"value":"0141-8955","type":"print"},{"value":"1573-2665","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,10,7]]},"assertion":[{"value":"2026-07-17","order":0,"name":"received","label":"Received","group":{"name":"publication_history","label":"Publication History"}},{"value":"2026-09-21","order":2,"name":"accepted","label":"Accepted","group":{"name":"publication_history","label":"Publication History"}},{"value":"2026-10-07","order":3,"name":"published","label":"Published","group":{"name":"publication_history","label":"Publication History"}}],"article-number":"e70257"}}