Identification of small molecules that improve ATP synthesis defects conferred by Leber's hereditary optic neuropathy mutations

摘要

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 mitochondria O-2 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. (C) 2016 Elsevier B.V. and Mitochondria Research Society. All rights reserved.