Screening of effective pharmacological treatments for MELAS syndrome using yeasts, fibroblasts and cybrid models of the disease
| Autor: | Juan Garrido Maraver, Cordero, Mario D., Irene Domínguez Monino, Sheila Pereira Arenas, Lechuga Vieco, Ana V., David, Cotan, Mario De La Mata, Manuel Oropesa Avila, Manuel De Miguel, Juan Bautista Lorite, Eloy Rivas Infante, Manuel Alvarez Dolado, Plácido, Navas, Sandra, Jackson, Francisci, Silvia, Sanchez Alcazar, Jose A. |
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| Rok vydání: | 2012 |
| Předmět: |
mitochondrial disease
riboflavin mitophagy melas coenzyme q10 RNA Transfer Leu Ubiquinone Riboflavin Drug Evaluation Preclinical Saccharomyces cerevisiae Fibroblasts Models Biological Research Papers Cell Line Genes Mitochondrial Mutation Autophagy MELAS Syndrome Humans Reactive Oxygen Species Cells Cultured |
| Zdroj: | British journal of pharmacology. 167(6) |
| ISSN: | 1476-5381 |
| Popis: | MELAS (mitochondrial encephalomyopathy, lactic acidosis and stroke-like episodes) is a mitochondrial disease most usually caused by point mutations in tRNA genes encoded by mitochondrial DNA (mtDNA). Approximately 80% of cases of MELAS syndrome are associated with a m.3243AG mutation in the MT-TL1 gene, which encodes the mitochondrial tRNALeu (UUR). Currently, no effective treatments are available for this chronic progressive disorder. Treatment strategies in MELAS and other mitochondrial diseases consist of several drugs that diminish the deleterious effects of the abnormal respiratory chain function, reduce the presence of toxic agents or correct deficiencies in essential cofactors.We evaluated the effectiveness of some common pharmacological agents that have been utilized in the treatment of MELAS, in yeast, fibroblast and cybrid models of the disease. The yeast model harbouring the A14G mutation in the mitochondrial tRNALeu(UUR) gene, which is equivalent to the A3243G mutation in humans, was used in the initial screening. Next, the most effective drugs that were able to rescue the respiratory deficiency in MELAS yeast mutants were tested in fibroblasts and cybrid models of MELAS disease.According to our results, supplementation with riboflavin or coenzyme Q(10) effectively reversed the respiratory defect in MELAS yeast and improved the pathologic alterations in MELAS fibroblast and cybrid cell models.Our results indicate that cell models have great potential for screening and validating the effects of novel drug candidates for MELAS treatment and presumably also for other diseases with mitochondrial impairment. |
| Databáze: | OpenAIRE |
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