Drug repositioning as a therapeutic strategy for neurodegenerations associated with OPA1 mutations

Serena J. Aleo, Valentina Del Dotto, Mario Fogazza, Alessandra Maresca, Tiziana Lodi, Paola Goffrini, Anna Ghelli, Michela Rugolo, Valerio Carelli, Enrico Baruffini, Claudia Zanna

Research output: Contribution to journalArticlepeer-review


OPA1 mutations are the major cause of dominant optic atrophy (DOA) and the syndromic form DOA plus, pathologies for which there is no established cure. We used a 'drug repurposing' approach to identify FDA-approved molecules able to rescue the mitochondrial dysfunctions induced by OPA1 mutations. We screened two different chemical libraries by using two yeast strains carrying the mgm1I322M and the chim3P646L mutations, identifying 26 drugs able to rescue their oxidative growth phenotype. Six of them, able to reduce the mitochondrial DNA instability in yeast, have been then tested in Opa1 deleted mouse embryonic fibroblasts expressing the human OPA1 isoform 1 bearing the R445H and D603H mutations. Some of these molecules were able to ameliorate the energetic functions and/or the mitochondrial network morphology, depending on the type of OPA1 mutation. The final validation has been performed in patients' fibroblasts, allowing to select the most effective molecules. Our current results are instrumental to rapidly translating the findings of this drug repurposing approach into clinical trial for DOA and other neurodegenerations caused by OPA1 mutations.

Original languageEnglish
Pages (from-to)3631-3645
Number of pages15
JournalHuman Molecular Genetics
Issue number22
Publication statusPublished - Jan 21 2021

ASJC Scopus subject areas

  • Molecular Biology
  • Genetics
  • Genetics(clinical)


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