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Mitochondrion. 2016 Sep;30:177-86. doi: 10.1016/j.mito.2016.08.002. Epub 2016 Aug 4.

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

Author information

1
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.
2
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.
3
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.

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.

KEYWORDS:

Complex I; High-throughput screening; LHON; Mitochondria

PMID:
27497748
PMCID:
PMC5039017
DOI:
10.1016/j.mito.2016.08.002
[Indexed for MEDLINE]
Free PMC Article

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