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

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


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.

MeSH terms

  • Adenosine Triphosphate / biosynthesis*
  • Cell Line
  • Drug Evaluation, Preclinical
  • Electron Transport Complex I / metabolism*
  • Humans
  • Metabolic Networks and Pathways / drug effects*
  • Optic Atrophy, Hereditary, Leber / drug therapy*
  • Papaverine / metabolism*
  • Pyridines / metabolism*
  • Zolpidem


  • Pyridines
  • Zolpidem
  • Adenosine Triphosphate
  • Papaverine
  • Electron Transport Complex I