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

Research output: Contribution to journalArticle

7 Scopus citations

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.

Original languageEnglish (US)
Pages (from-to)177-186
Number of pages10
JournalMitochondrion
Volume30
DOIs
StatePublished - Sep 1 2016

Keywords

  • Complex I
  • High-throughput screening
  • LHON
  • Mitochondria

ASJC Scopus subject areas

  • Molecular Medicine
  • Molecular Biology
  • Cell Biology

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