title: Identification of small molecules that improve ATP synthesis defects conferred by Leber's hereditary optic neuropathy mutations.
abstract: Inherited mitochondrial complex I mutations cause blinding Leber's hereditary optic neuropathy (LHON), for which no curative therapy exists. A specific biochemical consequence of LHON mutations in the presence of trace rotenone was observed: deficient complex I-dependent ATP synthesis (CIDAS) and mitochondrial O2 consumption, proportional to the clinical severity of the three primary LHON mutations. We optimized a high-throughput assay of CIDAS to screen 1600 drugs to 2, papaverine and zolpidem, which protected CIDAS in LHON cells concentration-dependently. TSPO and cAMP were investigated as protective mechanisms, but a conclusive mechanism remains to be elucidated; next steps include testing in animal models.
authors: Dept. of Molecular Biosciences, School of Veterinary Medicine, University of California, Davis, 1089 Veterinary Medicine Drive, Davis, CA 95616, United States. Electronic address: sddatta@ucdavis.edu.
authors: Sandipan
authors: S
authors: Datta
authors: Dept. of Molecular Biosciences, School of Veterinary Medicine, University of California, Davis, 1089 Veterinary Medicine Drive, Davis, CA 95616, United States. Electronic address: atomilov@ucdavis.edu.
authors: Alexey
authors: A
authors: Tomilov
authors: Dept. of Molecular Biosciences, School of Veterinary Medicine, University of California, Davis, 1089 Veterinary Medicine Drive, Davis, CA 95616, United States. Electronic address: gcortopassi@ucdavis.edu.
authors: Gino
authors: G
authors: Cortopassi
mesh_terms: D000255:Adenosine Triphosphate / Q000096:biosynthesis*; D002460:Cell Line; D004353:Drug Evaluation, Preclinical; D042967:Electron Transport Complex I / Q000378:metabolism*; D006801:Humans; D053858:Metabolic Networks and Pathways / Q000187:drug effects*; D029242:Optic Atrophy, Hereditary, Leber / Q000188:drug therapy*; D010208:Papaverine / Q000378:metabolism*; D011725:Pyridines / Q000378:metabolism*; D000077334:Zolpidem
chemical_list: D011725:Pyridines; D000077334:Zolpidem; D000255:Adenosine Triphosphate; D010208:Papaverine; D042967:Electron Transport Complex I
keywords: Complex I; High-throughput screening; LHON; Mitochondria