Screening strategy using a filamentous fungus model to repurpose drugs for mitochondrial complex I deficiencies
Year: 2026
Type: article
Abstract: 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.
Source: Life Sciences
Authors: Carole H. Sellem, Nolwenn Bounaix, Mathilde Logerais, Aurélie Renaud, Marc Alexandre d'Elia, Jeremy Richard, Claire Almyre, Guillaume Becker, Jordan Rivron, Anaïs Hoarau, Naïg Gueguen, Valérie Desquiret-Dumas, Aurore Inisan, Sophie Belal, Adélie Mellinger, François Godard, Véronique Paquis-Flucklinger, Olivier R. Baris, Stéphane Azoulay, Agnès Delahodde, Déborah Tribouillard-Tanvier, Nathalie Bonnefoy, Vincent Procaccio
Institutions: Centre National de la Recherche Scientifique, Commissariat à l'Énergie Atomique et aux Énergies Alternatives, Université Paris-Saclay, Institut de Biologie Intégrative de la Cellule, Inserm, Centre Hospitalier Universitaire d'Angers, Mitochondrial and Cardiovascular Physiopathology, Université d'Angers, Université Côte d'Azur, Institut de Chimie de Nice, Université de Bordeaux, Institut de Biochimie et Génétique Cellulaires, Laboratoire de pharmacologie et de toxicologie neurocardiovasculaire, Université de Strasbourg, Centre Hospitalier Universitaire de Nice, Institut de Recherche sur le Cancer et le Vieillissement de Nice
Language: English
Subfield: Molecular Biology
Domain: Life Sciences
Open Access status: hybrid
Estimated APC paid: $3,810
Award: G3163020192
OpenAlex ID: W7127354756