title: Screening of effective pharmacological treatments for MELAS syndrome using yeasts, fibroblasts and cybrid models of the disease.
abstract: OBJECTIVE
  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.
  
  
  METHODS
  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.
  
  
  RESULTS
  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.
  
  
  CONCLUSIONS
  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.
authors: Centro Andaluz de Biología del Desarrollo (CABD) and Centro de Investigación Biomédica en Red: Enfermedades Raras (CIBERER), Instituto de Salud Carlos III, Universidad Pablo de Olavide-Consejo Superior de Investigaciones Científicas-Junta de Andalucía, Sevilla, Spain.
authors: Juan
authors: J
authors: Garrido-Maraver
authors: Mario D
authors: MD
authors: Cordero
authors: Irene Domínguez
authors: ID
authors: Moñino
authors: Sheila
authors: S
authors: Pereira-Arenas
authors: Ana V
authors: AV
authors: Lechuga-Vieco
authors: David
authors: D
authors: Cotán
authors: Mario
authors: M
authors: De la Mata
authors: Manuel
authors: M
authors: Oropesa-Ávila
authors: Manuel
authors: M
authors: De Miguel
authors: Juan
authors: J
authors: Bautista Lorite
authors: Eloy
authors: E
authors: Rivas Infante
authors: Manuel
authors: M
authors: Alvarez-Dolado
authors: Plácido
authors: P
authors: Navas
authors: Sandra
authors: S
authors: Jackson
authors: Silvia
authors: S
authors: Francisci
authors: José A
authors: JA
authors: Sánchez-Alcázar
mesh_terms: D001343:Autophagy / Q000187:drug effects; D002460:Cell Line; D002478:Cells, Cultured; D004353:Drug Evaluation, Preclinical / Q000379:methods; D005347:Fibroblasts / Q000187:drug effects / Q000378:metabolism; D050259:Genes, Mitochondrial / Q000235:genetics; D006801:Humans; D017241:MELAS Syndrome / Q000188:drug therapy*; D008954:Models, Biological; D009154:Mutation; D012356:RNA, Transfer, Leu / Q000235:genetics; D017382:Reactive Oxygen Species; D012256:Riboflavin / Q000494:pharmacology; D012441:Saccharomyces cerevisiae; D014451:Ubiquinone / Q000031:analogs & derivatives / Q000494:pharmacology
chemical_list: D012356:RNA, Transfer, Leu; D017382:Reactive Oxygen Species; D014451:Ubiquinone; C024989:coenzyme Q10; D012256:Riboflavin