A yeast-based screening assay identifies repurposed drugs that suppress mitochondrial fusion and mtDNA maintenance defects
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 the...
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The Company of Biologists
2019-02-01
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doaj-172c34c3d9c34448913eb63a908833a12020-11-25T00:45:35ZengThe Company of BiologistsDisease Models & Mechanisms1754-84031754-84112019-02-0112210.1242/dmm.036558036558A yeast-based screening assay identifies repurposed drugs that suppress mitochondrial fusion and mtDNA maintenance defectsThomas Delerue0Déborah Tribouillard-Tanvier1Marlène Daloyau2Farnoosh Khosrobakhsh3Laurent Jean Emorine4Gaëlle Friocourt5Pascale Belenguer6Marc Blondel7Laetitia Arnauné-Pelloquin8 Research Center on Animal Cognition (CRCA) and Center of Developmental Biology (CBD), Center for Integrative Biology (CBI), Toulouse University, CNRS, UPS, 118 route de Narbonne, 31062 Toulouse, France Institut National de la Santé et de la Recherche Médicale UMR1078, Université de Bretagne Occidentale, Etablissement Français du Sang Bretagne, CHRU Brest, Hôpital Morvan, Laboratoire de Génétique Moléculaire, 29200 Brest, France Research Center on Animal Cognition (CRCA) and Center of Developmental Biology (CBD), Center for Integrative Biology (CBI), Toulouse University, CNRS, UPS, 118 route de Narbonne, 31062 Toulouse, France Research Center on Animal Cognition (CRCA) and Center of Developmental Biology (CBD), Center for Integrative Biology (CBI), Toulouse University, CNRS, UPS, 118 route de Narbonne, 31062 Toulouse, France Research Center on Animal Cognition (CRCA) and Center of Developmental Biology (CBD), Center for Integrative Biology (CBI), Toulouse University, CNRS, UPS, 118 route de Narbonne, 31062 Toulouse, France Institut National de la Santé et de la Recherche Médicale UMR1078, Université de Bretagne Occidentale, Etablissement Français du Sang Bretagne, CHRU Brest, Hôpital Morvan, Laboratoire de Génétique Moléculaire, 29200 Brest, France Research Center on Animal Cognition (CRCA) and Center of Developmental Biology (CBD), Center for Integrative Biology (CBI), Toulouse University, CNRS, UPS, 118 route de Narbonne, 31062 Toulouse, France Institut National de la Santé et de la Recherche Médicale UMR1078, Université de Bretagne Occidentale, Etablissement Français du Sang Bretagne, CHRU Brest, Hôpital Morvan, Laboratoire de Génétique Moléculaire, 29200 Brest, France Research Center on Animal Cognition (CRCA) and Center of Developmental Biology (CBD), Center for Integrative Biology (CBI), Toulouse University, CNRS, UPS, 118 route de Narbonne, 31062 Toulouse, France 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.http://dmm.biologists.org/content/12/2/dmm036558Mitochondrial fusionMitochondrial DNAHexestrolClomifeneYeastOPA1 |
collection |
DOAJ |
language |
English |
format |
Article |
sources |
DOAJ |
author |
Thomas Delerue Déborah Tribouillard-Tanvier Marlène Daloyau Farnoosh Khosrobakhsh Laurent Jean Emorine Gaëlle Friocourt Pascale Belenguer Marc Blondel Laetitia Arnauné-Pelloquin |
spellingShingle |
Thomas Delerue Déborah Tribouillard-Tanvier Marlène Daloyau Farnoosh Khosrobakhsh Laurent Jean Emorine Gaëlle Friocourt Pascale Belenguer Marc Blondel Laetitia Arnauné-Pelloquin A yeast-based screening assay identifies repurposed drugs that suppress mitochondrial fusion and mtDNA maintenance defects Disease Models & Mechanisms Mitochondrial fusion Mitochondrial DNA Hexestrol Clomifene Yeast OPA1 |
author_facet |
Thomas Delerue Déborah Tribouillard-Tanvier Marlène Daloyau Farnoosh Khosrobakhsh Laurent Jean Emorine Gaëlle Friocourt Pascale Belenguer Marc Blondel Laetitia Arnauné-Pelloquin |
author_sort |
Thomas Delerue |
title |
A yeast-based screening assay identifies repurposed drugs that suppress mitochondrial fusion and mtDNA maintenance defects |
title_short |
A yeast-based screening assay identifies repurposed drugs that suppress mitochondrial fusion and mtDNA maintenance defects |
title_full |
A yeast-based screening assay identifies repurposed drugs that suppress mitochondrial fusion and mtDNA maintenance defects |
title_fullStr |
A yeast-based screening assay identifies repurposed drugs that suppress mitochondrial fusion and mtDNA maintenance defects |
title_full_unstemmed |
A yeast-based screening assay identifies repurposed drugs that suppress mitochondrial fusion and mtDNA maintenance defects |
title_sort |
yeast-based screening assay identifies repurposed drugs that suppress mitochondrial fusion and mtdna maintenance defects |
publisher |
The Company of Biologists |
series |
Disease Models & Mechanisms |
issn |
1754-8403 1754-8411 |
publishDate |
2019-02-01 |
description |
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. |
topic |
Mitochondrial fusion Mitochondrial DNA Hexestrol Clomifene Yeast OPA1 |
url |
http://dmm.biologists.org/content/12/2/dmm036558 |
work_keys_str_mv |
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