{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,11,3]],"date-time":"2026-11-03T22:39:24Z","timestamp":1793745564543,"version":"4.6.1"},"reference-count":67,"publisher":"American Society for Clinical Investigation","issue":"20","license":[{"start":{"date-parts":[[2022,10,24]],"date-time":"2022-10-24T00:00:00Z","timestamp":1666569600000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/100000002","name":"National Institutes of Health","doi-asserted-by":"crossref","award":["P400OD010440,R01-GM120762,R35-GM134863,T32-GM008638"],"award-info":[{"award-number":["P400OD010440,R01-GM120762,R35-GM134863,T32-GM008638"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"crossref"}]},{"DOI":"10.13039\/100006458","name":"Children\u2019s Hospital of Philadelphia","doi-asserted-by":"crossref","award":["Mitochondrial Medicine Frontier Program"],"award-info":[{"award-number":["Mitochondrial Medicine Frontier Program"]}],"id":[{"id":"10.13039\/100006458","id-type":"DOI","asserted-by":"crossref"}]},{"DOI":"10.13039\/100006458","name":"Children\u2019s Hospital of Philadelphia","doi-asserted-by":"crossref","award":["Josh Cohen,DLD Research Fund"],"award-info":[{"award-number":["Josh Cohen,DLD Research Fund"]}],"id":[{"id":"10.13039\/100006458","id-type":"DOI","asserted-by":"crossref"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2022,10,24]]},"abstract":"<jats:p>\n                    Dihydrolipoamide dehydrogenase (DLD) deficiency is a recessive mitochondrial disorder caused by depletion of DLD from \u03b1-ketoacid dehydrogenase complexes.\n                    <jats:italic>Caenorhabditis elegans<\/jats:italic>\n                    animal models of DLD deficiency generated by graded feeding of\n                    <jats:italic>dld-1(RNAi)<\/jats:italic>\n                    revealed that full or partial reduction of DLD-1 expression recapitulated increased pyruvate levels typical of pyruvate dehydrogenase complex deficiency and significantly altered animal survival and health, with reductions in brood size, adult length, and neuromuscular function. DLD-1 deficiency dramatically increased mitochondrial unfolded protein stress response induction and adaptive mitochondrial proliferation. While ATP levels were reduced, respiratory chain enzyme activities and in vivo mitochondrial membrane potential were not significantly altered. DLD-1 depletion directly correlated with the induction of mitochondrial stress and impairment of worm growth and neuromuscular function. The safety and efficacy of dichloroacetate, thiamine, riboflavin, 5-aminoimidazole-4-carboxamide-1-\u03b2-d-ribofuranoside (AICAR), l-carnitine, and lipoic acid supplemental therapies empirically used for human\n                    <jats:italic>DLD<\/jats:italic>\n                    disease were objectively evaluated by life span and mitochondrial stress response studies. Only dichloroacetate and thiamine showed individual and synergistic therapeutic benefits. Collectively, these\n                    <jats:italic>C. elegans dld-1(RNAi)<\/jats:italic>\n                    animal model studies demonstrate the translational relevance of preclinical modeling of disease mechanisms and therapeutic candidates. Results suggest that clinical trials are warranted to evaluate the safety and efficacy of dichloroacetate and thiamine in human\n                    <jats:italic>DLD<\/jats:italic>\n                    disease.\n                  <\/jats:p>","DOI":"10.1172\/jci.insight.156222","type":"journal-article","created":{"date-parts":[[2022,10,23]],"date-time":"2022-10-23T14:00:56Z","timestamp":1666533656000},"source":"Crossref","is-referenced-by-count":30,"title":["Dichloroacetate and thiamine improve survival and mitochondrial stress in a C. elegans model of dihydrolipoamide dehydrogenase deficiency"],"prefix":"10.1172","volume":"7","author":[{"given":"Chynna N.","family":"Broxton","sequence":"first","affiliation":[{"name":"Mitochondrial Medicine Frontier Program, Division of Human Genetics, Department of Pediatrics, Children\u2019s Hospital of Philadelphia, Philadelphia, Pennsylvania, 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