{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,30]],"date-time":"2026-07-30T14:44:12Z","timestamp":1785422652986,"version":"3.56.0"},"reference-count":107,"publisher":"MDPI AG","issue":"8","license":[{"start":{"date-parts":[[2024,8,22]],"date-time":"2024-08-22T00:00:00Z","timestamp":1724284800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100004587","name":"Instituto de Salud Carlos III","doi-asserted-by":"publisher","award":["FIS PI19\/00377 (2019) and FIS PI22\/00142 (2022)"],"award-info":[{"award-number":["FIS PI19\/00377 (2019) and FIS PI22\/00142 (2022)"]}],"id":[{"id":"10.13039\/501100004587","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100011011","name":"Junta de Andaluc\u00eda","doi-asserted-by":"publisher","award":["CTS-5725, PY18-850 and UPO-FEDER 2018 (UPO-1380614)"],"award-info":[{"award-number":["CTS-5725, PY18-850 and UPO-FEDER 2018 (UPO-1380614)"]}],"id":[{"id":"10.13039\/501100011011","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Antioxidants"],"abstract":"<jats:p>Mutations in the lipoyltransferase 1 (LIPT1) gene are rare inborn errors of metabolism leading to a fatal condition characterized by lipoylation defects of the 2-ketoacid dehydrogenase complexes causing early-onset seizures, psychomotor retardation, abnormal muscle tone, severe lactic acidosis, and increased urine lactate, ketoglutarate, and 2-oxoacid levels. In this article, we characterized the disease pathophysiology using fibroblasts and induced neurons derived from a patient bearing a compound heterozygous mutation in LIPT1. A Western blot analysis revealed a reduced expression of LIPT1 and absent expression of lipoylated pyruvate dehydrogenase E2 (PDH E2) and alpha-ketoglutarate dehydrogenase E2 (\u03b1-KGDH E2) subunits. Accordingly, activities of PDH and \u03b1-KGDH were markedly reduced, associated with cell bioenergetics failure, iron accumulation, and lipid peroxidation. In addition, using a pharmacological screening, we identified a cocktail of antioxidants and mitochondrial boosting agents consisting of pantothenate, nicotinamide, vitamin E, thiamine, biotin, and \u03b1-lipoic acid, which is capable of rescuing LIPT1 pathophysiology, increasing the LIPT1 expression and lipoylation of mitochondrial proteins, improving cell bioenergetics, and eliminating iron overload and lipid peroxidation. Furthermore, our data suggest that the beneficial effect of the treatment is mainly mediated by SIRT3 activation. In conclusion, we have identified a promising therapeutic approach for correcting LIPT1 mutations.<\/jats:p>","DOI":"10.3390\/antiox13081023","type":"journal-article","created":{"date-parts":[[2024,8,22]],"date-time":"2024-08-22T06:28:51Z","timestamp":1724308131000},"page":"1023","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":8,"title":["A Multi-Target Pharmacological Correction of a Lipoyltransferase LIPT1 Gene Mutation in Patient-Derived Cellular Models"],"prefix":"10.3390","volume":"13","author":[{"given":"David","family":"G\u00f3mez-Fern\u00e1ndez","sequence":"first","affiliation":[{"name":"Centro Andaluz de Biolog\u00eda del Desarrollo (CABD-CSIC-Universidad Pablo de Olavide), 41013 Sevilla, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ana","family":"Romero-Gonz\u00e1lez","sequence":"additional","affiliation":[{"name":"Centro Andaluz de Biolog\u00eda del Desarrollo (CABD-CSIC-Universidad Pablo de Olavide), 41013 Sevilla, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Juan M.","family":"Su\u00e1rez-Rivero","sequence":"additional","affiliation":[{"name":"Centro Andaluz de Biolog\u00eda del Desarrollo (CABD-CSIC-Universidad Pablo de Olavide), 41013 Sevilla, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Paula","family":"Cilleros-Holgado","sequence":"additional","affiliation":[{"name":"Centro Andaluz de Biolog\u00eda del Desarrollo (CABD-CSIC-Universidad Pablo de Olavide), 41013 Sevilla, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"M\u00f3nica","family":"\u00c1lvarez-C\u00f3rdoba","sequence":"additional","affiliation":[{"name":"Centro Andaluz de Biolog\u00eda del Desarrollo (CABD-CSIC-Universidad Pablo de Olavide), 41013 Sevilla, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Roc\u00edo","family":"Pi\u00f1ero-P\u00e9rez","sequence":"additional","affiliation":[{"name":"Centro Andaluz de Biolog\u00eda del Desarrollo (CABD-CSIC-Universidad Pablo de Olavide), 41013 Sevilla, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jos\u00e9 Manuel","family":"Romero-Dom\u00ednguez","sequence":"additional","affiliation":[{"name":"Centro Andaluz de Biolog\u00eda del Desarrollo (CABD-CSIC-Universidad Pablo de Olavide), 41013 Sevilla, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Diana","family":"Reche-L\u00f3pez","sequence":"additional","affiliation":[{"name":"Centro Andaluz de Biolog\u00eda del Desarrollo (CABD-CSIC-Universidad Pablo de Olavide), 41013 Sevilla, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0005-5906-1662","authenticated-orcid":false,"given":"Alejandra","family":"L\u00f3pez-Cabrera","sequence":"additional","affiliation":[{"name":"Centro Andaluz de Biolog\u00eda del Desarrollo (CABD-CSIC-Universidad Pablo de Olavide), 41013 Sevilla, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4582-6511","authenticated-orcid":false,"given":"Salvador","family":"Ib\u00e1\u00f1ez-Mico","sequence":"additional","affiliation":[{"name":"Hospital Cl\u00ednico Universitario Virgen de la Arrixaca, Servicio de Neuropediatr\u00eda, 30120 Murcia, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Marta","family":"Castro de Oliveira","sequence":"additional","affiliation":[{"name":"Neuropediatria, Neurolinkia, C. Jard\u00edn de la Isla, 8, Local 4 y 5, 41014 Sevilla, Spain"},{"name":"FEA Pediatr\u00eda, Centro Universitario Hospitalar de Faro, R. Le\u00e3o Penedo, 8000-386 Faro, Portugal"},{"name":"Neuropediatria, Servicio de Pediatr\u00eda, Hospital Universitario Virgen Macarena, 41009 Sevilla, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Andr\u00e9s","family":"Rodr\u00edguez-Sacrist\u00e1n","sequence":"additional","affiliation":[{"name":"Neuropediatria, Servicio de Pediatr\u00eda, Hospital Universitario Virgen Macarena, 41009 Sevilla, Spain"},{"name":"Departamento de Farmacolog\u00eda, Radiolog\u00eda y Pediatr\u00eda de la Facultad de Medicina de la Universidad de Sevilla, 41009 Sevilla, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1531-550X","authenticated-orcid":false,"given":"Susana","family":"Gonz\u00e1lez-Granero","sequence":"additional","affiliation":[{"name":"Laboratory of Comparative Neurobiology, Cavanilles Institute of Biodiversity and Evolutionary Biology, University of Valencia and CIBERNED-ISCIII, 46980 Valencia, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9872-6499","authenticated-orcid":false,"given":"Jos\u00e9 Manuel","family":"Garc\u00eda-Verdugo","sequence":"additional","affiliation":[{"name":"Laboratory of Comparative Neurobiology, Cavanilles Institute of Biodiversity and Evolutionary Biology, University of Valencia and CIBERNED-ISCIII, 46980 Valencia, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9705-1469","authenticated-orcid":false,"given":"Jos\u00e9 A.","family":"S\u00e1nchez-Alc\u00e1zar","sequence":"additional","affiliation":[{"name":"Centro Andaluz de Biolog\u00eda del Desarrollo (CABD-CSIC-Universidad Pablo de Olavide), 41013 Sevilla, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2024,8,22]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"5919","DOI":"10.1021\/ja01156a566","article-title":"Crystallization of a Derivative of Protogen-B","volume":"73","author":"Patterson","year":"2002","journal-title":"J. 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