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© 2024 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https://creativecommons.org/licenses/by/4.0/). Notwithstanding the ProQuest Terms and Conditions, you may use this content in accordance with the terms of the License.

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 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 (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 α-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.

Details

Title
A Multi-Target Pharmacological Correction of a Lipoyltransferase LIPT1 Gene Mutation in Patient-Derived Cellular Models
Author
Gómez-Fernández, David 1 ; Romero-González, Ana 1 ; Suárez-Rivero, Juan M 1 ; Cilleros-Holgado, Paula 1 ; Álvarez-Córdoba, Mónica 1 ; Piñero-Pérez, Rocío 1 ; Romero-Domínguez, José Manuel 1 ; Reche-López, Diana 1 ; López-Cabrera, Alejandra 1   VIAFID ORCID Logo  ; Ibáñez-Mico, Salvador 2   VIAFID ORCID Logo  ; Castro de Oliveira, Marta 3 ; Rodríguez-Sacristán, Andrés 4 ; González-Granero, Susana 5   VIAFID ORCID Logo  ; García-Verdugo, José Manuel 5   VIAFID ORCID Logo  ; Sánchez-Alcázar, José A 1   VIAFID ORCID Logo 

 Centro Andaluz de Biología del Desarrollo (CABD-CSIC-Universidad Pablo de Olavide), 41013 Sevilla, Spain; [email protected] (D.G.-F.); [email protected] (A.R.-G.); [email protected] (J.M.S.-R.); [email protected] (P.C.-H.); [email protected] (M.Á.-C.); [email protected] (R.P.-P.); [email protected] (J.M.R.-D.); [email protected] (D.R.-L.); [email protected] (A.L.-C.) 
 Hospital Clínico Universitario Virgen de la Arrixaca, Servicio de Neuropediatría, 30120 Murcia, Spain; [email protected] 
 Neuropediatria, Neurolinkia, C. Jardín de la Isla, 8, Local 4 y 5, 41014 Sevilla, Spain; [email protected]; FEA Pediatría, Centro Universitario Hospitalar de Faro, R. Leão Penedo, 8000-386 Faro, Portugal; Neuropediatria, Servicio de Pediatría, Hospital Universitario Virgen Macarena, 41009 Sevilla, Spain; [email protected] 
 Neuropediatria, Servicio de Pediatría, Hospital Universitario Virgen Macarena, 41009 Sevilla, Spain; [email protected]; Departamento de Farmacología, Radiología y Pediatría de la Facultad de Medicina de la Universidad de Sevilla, 41009 Sevilla, Spain 
 Laboratory of Comparative Neurobiology, Cavanilles Institute of Biodiversity and Evolutionary Biology, University of Valencia and CIBERNED-ISCIII, 46980 Valencia, Spain; [email protected] (S.G.-G.); [email protected] (J.M.G.-V.) 
First page
1023
Publication year
2024
Publication date
2024
Publisher
MDPI AG
e-ISSN
20763921
Source type
Scholarly Journal
Language of publication
English
ProQuest document ID
3097811611
Copyright
© 2024 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https://creativecommons.org/licenses/by/4.0/). Notwithstanding the ProQuest Terms and Conditions, you may use this content in accordance with the terms of the License.