A yeast-based screening assay identifies repurposed drugs that suppress mitochondrial fusion and mtDNA maintenance defects

Abstract

Mitochondria continually move, fuse and divide and these dynamics are essential for the proper function of these organelles. Indeed, the dynamic balance of fusion and fission of mitochondria determines their morphology and allows their immediate adaptation to energetic needs as well as preserving their integrity. As a consequence, mitochondrial fusion and fission dynamics and the proteins that control these processes, which are conserved from yeast to human, are essential and their disturbances are associated with severe human disorders, including neurodegenerative diseases. For example, mutations in OPA1, that encodes a conserved factor essential for mitochondrial fusion, lead to Optic Atrophy 1, a neurodegeneration that affects the optic nerve eventually leading to blindness. Here, by screening a collection of ∼1,600 repurposed drugs on a fission yeast model, we identified five compounds able to efficiently prevent the lethality associated to the loss of Msp1p, the fission yeast orthologue of OPA1. One compound, hexestrol, was able to rescue both the mitochondrial fragmentation and mtDNA depletion induced by the loss of Msp1p, whereas the second, clomifene, only suppressed the mtDNA defect. Since yeast was already successfully used to identify candidate drugs to treat inherited mitochondrial diseases, this work may provide useful leads for the treatment of optic atrophies such as Optic Atrophy 1 or Leber Hereditary Optic Neuropathy.