Version 1
: Received: 22 July 2024 / Approved: 22 July 2024 / Online: 22 July 2024 (14:19:16 CEST)
How to cite:
Gómez-Fernández, D.; Romero-González, A.; Suárez-Rivero, J. M.; Cilleros-Holgado, P.; Álvarez-Córdoba, M.; Piñero-Pérez, R.; Romero-Domínguez, J. M.; Reche-López, D.; López-Cabrera, A.; Ibañez-Mico, S.; Castro de Oliveira, M.; Rodríguez-Sacristán, A.; Gónzalez-Granero, S.; García-Verdugo, J. M.; Sánchez-Alcázar, J. A. A Multi-target Pharmacological Correction of a Lipoyltransferase LIPT1 Gene Mutation in Patient-Derived Cellular Models. Preprints2024, 2024071743. https://doi.org/10.20944/preprints202407.1743.v1
Gómez-Fernández, D.; Romero-González, A.; Suárez-Rivero, J. M.; Cilleros-Holgado, P.; Álvarez-Córdoba, M.; Piñero-Pérez, R.; Romero-Domínguez, J. M.; Reche-López, D.; López-Cabrera, A.; Ibañez-Mico, S.; Castro de Oliveira, M.; Rodríguez-Sacristán, A.; Gónzalez-Granero, S.; García-Verdugo, J. M.; Sánchez-Alcázar, J. A. A Multi-target Pharmacological Correction of a Lipoyltransferase LIPT1 Gene Mutation in Patient-Derived Cellular Models. Preprints 2024, 2024071743. https://doi.org/10.20944/preprints202407.1743.v1
Gómez-Fernández, D.; Romero-González, A.; Suárez-Rivero, J. M.; Cilleros-Holgado, P.; Álvarez-Córdoba, M.; Piñero-Pérez, R.; Romero-Domínguez, J. M.; Reche-López, D.; López-Cabrera, A.; Ibañez-Mico, S.; Castro de Oliveira, M.; Rodríguez-Sacristán, A.; Gónzalez-Granero, S.; García-Verdugo, J. M.; Sánchez-Alcázar, J. A. A Multi-target Pharmacological Correction of a Lipoyltransferase LIPT1 Gene Mutation in Patient-Derived Cellular Models. Preprints2024, 2024071743. https://doi.org/10.20944/preprints202407.1743.v1
APA Style
Gómez-Fernández, D., Romero-González, A., Suárez-Rivero, J. M., Cilleros-Holgado, P., Álvarez-Córdoba, M., Piñero-Pérez, R., Romero-Domínguez, J. M., Reche-López, D., López-Cabrera, A., Ibañez-Mico, S., Castro de Oliveira, M., Rodríguez-Sacristán, A., Gónzalez-Granero, S., García-Verdugo, J. M., & Sánchez-Alcázar, J. A. (2024). A Multi-target Pharmacological Correction of a Lipoyltransferase LIPT1 Gene Mutation in Patient-Derived Cellular Models. Preprints. https://doi.org/10.20944/preprints202407.1743.v1
Chicago/Turabian Style
Gómez-Fernández, D., José Manuel García-Verdugo and José A Sánchez-Alcázar. 2024 "A Multi-target Pharmacological Correction of a Lipoyltransferase LIPT1 Gene Mutation in Patient-Derived Cellular Models" Preprints. https://doi.org/10.20944/preprints202407.1743.v1
Abstract
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 aci-dosis and increased urine lactate, ketoglutarate, and 2-oxoacids 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. Western blot analysis revealed reduced expression of LIPT1 and absent expression of lipoylated pyruvate dehydrogenase E2 (PDH E2) and alpha-ketoglutarate dehydrogenase E2 (α-KGDH E2) subunits. Accordingly, activities of PDH and α-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 alpha-lipoic acid, which is capable of rescuing LIPT1 patho-physiology, increasing 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.
Biology and Life Sciences, Neuroscience and Neurology
Copyright:
This is an open access article distributed under the Creative Commons Attribution License which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.
