{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,8]],"date-time":"2026-10-08T18:12:50Z","timestamp":1791483170461,"version":"4.3.4"},"reference-count":61,"publisher":"American Society for Clinical Investigation","issue":"18","license":[{"start":{"date-parts":[[2024,9,24]],"date-time":"2024-09-24T00:00:00Z","timestamp":1727136000000},"content-version":"vor","delay-in-days":35,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/100000002","name":"National institutes of health","doi-asserted-by":"crossref","award":["R35-GM134863"],"award-info":[{"award-number":["R35-GM134863"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"crossref"}]},{"name":"Philanthropic fund","award":["Josh Cohen Research Fund"],"award-info":[{"award-number":["Josh Cohen Research Fund"]}]},{"name":"Saol Therapeutics","award":["Sponsored Research Agreement"],"award-info":[{"award-number":["Sponsored Research Agreement"]}]},{"name":"Stealth BioTherapeutics","award":["Sponsored Research Agreement"],"award-info":[{"award-number":["Sponsored Research Agreement"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2024,9,24]]},"abstract":"<jats:p>\n                    Dihydrolipoamide dehydrogenase (DLD) deficiency is a recessive mitochondrial disease caused by variants in\n                    <jats:italic>DLD<\/jats:italic>\n                    , the E\n                    <jats:sub>3<\/jats:sub>\n                    subunit of mitochondrial \u03b1-keto (or 2-oxo) acid dehydrogenase complexes. DLD disease symptoms are multisystemic, variably manifesting as Leigh syndrome, neurodevelopmental disability, seizures, cardiomyopathy, liver disease, fatigue, and lactic acidemia. While most DLD disease symptoms are attributed to dysfunction of the pyruvate dehydrogenase complex, the effects of other \u03b1-keto acid dehydrogenase deficiencies remain unclear. Current therapies for DLD deficiency are ineffective, with no vertebrate animal model available for preclinical study. We created a viable\n                    <jats:italic>Danio rerio<\/jats:italic>\n                    (zebrafish) KO model of DLD deficiency,\n                    <jats:italic>\n                      dldh\n                      <jats:sup>cri3<\/jats:sup>\n                    <\/jats:italic>\n                    . Detailed phenotypic characterization revealed shortened larval survival, uninflated swim bladder, hepatomegaly and fatty liver, and reduced swim activity. These animals displayed increased pyruvate and lactate levels, with severe disruption of branched-chain amino acid catabolism manifest as increased valine, leucine, isoleucine, \u03b1-ketoisovalerate, and \u03b1-ketoglutarate levels. Evaluation of mitochondrial ultrastructure revealed gross enlargement, severe cristae disruption, and reduction in matrix electron density in liver, intestines, and muscle. Therapeutic modeling of candidate therapies demonstrated that probucol or thiamine improved larval swim activity. Overall, this vertebrate model demonstrated characteristic phenotypic and metabolic alterations of DLD disease, offering a robust platform to screen and characterize candidate therapies.\n                  <\/jats:p>","DOI":"10.1172\/jci.insight.178973","type":"journal-article","created":{"date-parts":[[2024,8,20]],"date-time":"2024-08-20T12:00:13Z","timestamp":1724155213000},"source":"Crossref","is-referenced-by-count":16,"title":["dldhcri3 zebrafish exhibit altered mitochondrial ultrastructure, morphology, and dysfunction partially rescued by probucol or thiamine"],"prefix":"10.1172","volume":"9","author":[{"given":"Manuela","family":"Lavorato","sequence":"first","affiliation":[{"name":"Mitochondrial Medicine Frontier Program, Division of Human Genetics, Department of Pediatrics, The Children\u2019s Hospital of Philadelphia (CHOP), Philadelphia, Pennsylvania, USA."},{"name":"Department of Pediatrics 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