title: A yeast-based assay identifies drugs active against human mitochondrial disorders.
abstract: Due to the lack of relevant animal models, development of effective treatments for human mitochondrial diseases has been limited. Here we establish a rapid, yeast-based assay to screen for drugs active against human inherited mitochondrial diseases affecting ATP synthase, in particular NARP (neuropathy, ataxia, and retinitis pigmentosa) syndrome. This method is based on the conservation of mitochondrial function from yeast to human, on the unique ability of yeast to survive without production of ATP by oxidative phosphorylation, and on the amenability of the yeast mitochondrial genome to site-directed mutagenesis. Our method identifies chlorhexidine by screening a chemical library and oleate through a candidate approach. We show that these molecules rescue a number of phenotypes resulting from mutations affecting ATP synthase in yeast. These compounds are also active on human cybrid cells derived from NARP patients. These results validate our method as an effective high-throughput screening approach to identify drugs active in the treatment of human ATP synthase disorders and suggest that this type of method could be applied to other mitochondrial diseases.
authors.affiliation: INSERM U613; Université de Brest, Faculté de Médecine et des Sciences de la Santé; Etablissement Français du Sang (EFS) Bretagne; Centre Hospitalier Régional Universitaire Brest, Hop Morvan, Laboratoire de Génétique Moléculaire, F-29200 Brest, France.
authors.forename: Elodie
authors.initials: E
authors.lastname: Couplan
authors.forename: Raeka S
authors.initials: RS
authors.lastname: Aiyar
authors.forename: Roza
authors.initials: R
authors.lastname: Kucharczyk
authors.forename: Anna
authors.initials: A
authors.lastname: Kabala
authors.forename: Nahia
authors.initials: N
authors.lastname: Ezkurdia
authors.forename: Julien
authors.initials: J
authors.lastname: Gagneur
authors.forename: Robert P
authors.initials: RP
authors.lastname: St Onge
authors.forename: Bénédicte
authors.initials: B
authors.lastname: Salin
authors.forename: Flavie
authors.initials: F
authors.lastname: Soubigou
authors.forename: Marie
authors.initials: M
authors.lastname: Le Cann
authors.forename: Lars M
authors.initials: LM
authors.lastname: Steinmetz
authors.forename: Jean-Paul
authors.initials: JP
authors.lastname: di Rago
authors.forename: Marc
authors.initials: M
authors.lastname: Blondel
mesh_terms: D002460:Cell Line; D002710:Chlorhexidine / Q000494:pharmacology* / Q000627:therapeutic use; D055808:Drug Discovery / Q000379:methods*; D004353:Drug Evaluation, Preclinical / Q000379:methods*; D020869:Gene Expression Profiling; D006801:Humans; D017240:Mitochondrial Myopathies / Q000188:drug therapy*; D025261:Mitochondrial Proton-Translocating ATPases / Q000235:genetics*; D016297:Mutagenesis, Site-Directed; D009154:Mutation / Q000235:genetics; D019301:Oleic Acid / Q000494:pharmacology* / Q000627:therapeutic use; D012174:Retinitis Pigmentosa / Q000188:drug therapy*; D004718:Saccharomycetales
chemical_list: D019301:Oleic Acid; D025261:Mitochondrial Proton-Translocating ATPases; D002710:Chlorhexidine