Life sciences · 2026
Screening strategy using a filamentous fungus model to repurpose drugs for mitochondrial complex I deficiencies.
СтатьяНазвание и аннотация: Перевод в очереди
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Sellem Carole H, Bounaix Nolwenn, Logerais Mathilde, Renaud Aurélie, d'Elia Marc Alexandre, Richard Jeremy, Almyre Claire, Becker Guillaume, Rivron Jordan, Hoarau Anaïs, Gueguen Naïg, Desquiret-Dumas Valérie, Inisan Aurore, Belal Sophie, Mellinger Adélie, Godard François, Paquis-Flucklinger Véronique, Baris Olivier R, Azoulay Stéphane, Delahodde Agnès, Tribouillard-Tanvier Déborah, Bonnefoy Nathalie, Procaccio Vincent
Аннотация
AIM: This study aimed to repurpose FDA-approved drugs for the treatment of mitochondrial complex I diseases.
MATERIALS AND METHODS: The NUO-51 protein of the filamentous fungus Podospora anserina is the homolog of the human key catalytic subunit of complex I, NDUFV1. By introducing a pathogenic mutation into P. anserina NUO-51 we created a novel model of complex I deficiency targeting the NDUFV1 subunit. The thermosensitive phenotype of the fungal mutant enabled us to screen a library of nearly one thousand FDA-approved molecules. We have implemented various techniques such as growth analysis, oxygen consumption measurements, complex I activity assays and western blotting on Podospora, Caenorhabditis elegans and human on equivalent NDUFV1 mutant models, treated or untreated with the most effective drugs found during the screen.
KEY FINDINGS: We isolated a series of compounds able to rescue the growth defect of the Podospora nuo-51 mutant, including ligands of serotonin receptors or transporters. Among the selected drugs, alverine citrate (ALV) and dapoxetine hydrochloride (DAP) emerged as the most active drugs. Both drugs enhanced respiration and complex I activity, not only in the Podospora mutant, but also in Caenorhabditis elegans worms deficient for the NDUFV1 ortholog and in fibroblasts from patient carrying NDUFV1 mutations.
SIGNIFICANCE: Together, our work demonstrates the usefulness of Podospora anserina as fungal model for identifying promising therapeutic candidates for complex I diseases, paving the way for future clinical trials.
MATERIALS AND METHODS: The NUO-51 protein of the filamentous fungus Podospora anserina is the homolog of the human key catalytic subunit of complex I, NDUFV1. By introducing a pathogenic mutation into P. anserina NUO-51 we created a novel model of complex I deficiency targeting the NDUFV1 subunit. The thermosensitive phenotype of the fungal mutant enabled us to screen a library of nearly one thousand FDA-approved molecules. We have implemented various techniques such as growth analysis, oxygen consumption measurements, complex I activity assays and western blotting on Podospora, Caenorhabditis elegans and human on equivalent NDUFV1 mutant models, treated or untreated with the most effective drugs found during the screen.
KEY FINDINGS: We isolated a series of compounds able to rescue the growth defect of the Podospora nuo-51 mutant, including ligands of serotonin receptors or transporters. Among the selected drugs, alverine citrate (ALV) and dapoxetine hydrochloride (DAP) emerged as the most active drugs. Both drugs enhanced respiration and complex I activity, not only in the Podospora mutant, but also in Caenorhabditis elegans worms deficient for the NDUFV1 ortholog and in fibroblasts from patient carrying NDUFV1 mutations.
SIGNIFICANCE: Together, our work demonstrates the usefulness of Podospora anserina as fungal model for identifying promising therapeutic candidates for complex I diseases, paving the way for future clinical trials.