RT Journal Article
SR Electronic
T1 A yeast-based screening assay identifies repurposed drugs that suppress mitochondrial fusion and mtDNA maintenance defects
JF Disease Models & Mechanisms
JO Dis Models Mech
FD The Company of Biologists Limited
SP dmm036558
DO 10.1242/dmm.036558
VO 12
IS 2
A1 Delerue, Thomas
A1 Tribouillard-Tanvier, Déborah
A1 Daloyau, Marlène
A1 Khosrobakhsh, Farnoosh
A1 Emorine, Laurent Jean
A1 Friocourt, Gaëlle
A1 Belenguer, Pascale
A1 Blondel, Marc
A1 Arnauné-Pelloquin, Laetitia
YR 2019
UL http://dmm.biologists.org/content/12/2/dmm036558.abstract
AB Mitochondria continually move, fuse and divide, and these dynamics are essential for the proper function of the 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, which 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 ∼1600 repurposed drugs on a fission yeast model, we identified five compounds able to efficiently prevent the lethality associated with the loss of Msp1p, the fission yeast ortholog of OPA1. One compound, hexestrol, was able to rescue both the mitochondrial fragmentation and mitochondrial DNA (mtDNA) depletion induced by the loss of Msp1p, whereas the second, clomifene, only suppressed the mtDNA defect. Yeast has already been successfully used to identify candidate drugs to treat inherited mitochondrial diseases; this work may therefore provide useful leads for the treatment of optic atrophies such as optic atrophy 1 or Leber hereditary optic neuropathy.