Screening of effective pharmacological treatments for MELAS syndrome using yeasts, fibroblasts and cybrid models of the disease

• Published in: British journal of pharmacology Vol. 167; no. 6; pp. 1311 - 1328
• Main Authors: Garrido‐Maraver, Juan, Cordero, Mario D, Moñino, Irene Domínguez, Pereira‐Arenas, Sheila, Lechuga‐Vieco, Ana V, Cotán, David, De la Mata, Mario, Oropesa‐Ávila, Manuel, De Miguel, Manuel, Bautista Lorite, Juan, Rivas Infante, Eloy, Álvarez‐Dolado, Manuel, Navas, Plácido, Jackson, Sandra, Francisci, Silvia, Sánchez‐Alcázar, José A
• Format: Journal Article
• Language: English
• Published: Oxford, UK Blackwell Publishing Ltd 01.11.2012; Nature Publishing Group
• Subjects: Autophagy - drug effects; Biological and medical sciences; Cell Line; Cells, Cultured; coenzyme Q10; Disease; Drug Evaluation, Preclinical - methods; Errors of metabolism; Fibroblasts; Fibroblasts - drug effects; Fibroblasts - metabolism; Genes, Mitochondrial - genetics; Humans; Medical sciences; MELAS; MELAS Syndrome - drug therapy; Metabolic diseases; Miscellaneous hereditary metabolic disorders; mitochondrial disease; mitophagy; Models, Biological; Mutation; Pharmacology. Drug treatments; Reactive Oxygen Species; Research Papers; riboflavin; Riboflavin - pharmacology; RNA, Transfer, Leu - genetics; Saccharomyces cerevisiae; Ubiquinone - analogs & derivatives; Ubiquinone - pharmacology; Yeast; Pharmacotherapy; Riboflavin; Metabolic diseases; B-Vitamins; MELAS; mitophagy; Antioxidant; Enzymopathy; Mitochondrial disorder; mitochondrial disease; Genetic disease; Screening; Treatment; Ubiquinone; Models; MELAS syndrome; Fibroblast; coenzyme Q
• ISSN: 0007-1188; 1476-5381
• DOI: 10.1111/j.1476-5381.2012.02086.x

BACKGROUND AND PURPOSE 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.3243A > G 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. EXPERIMENTAL APPROACH 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. KEY RESULTS According to our results, supplementation with riboflavin or coenzyme Q10 effectively reversed the respiratory defect in MELAS yeast and improved the pathologic alterations in MELAS fibroblast and cybrid cell models. CONCLUSIONS AND IMPLICATIONS 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.