Ebselen restores mitochondrial function through metabolic rewiring in Barth syndrome and related mitochondrial diseases

Abstract Despite major advances in the genetic diagnosis of mitochondrial disorders, effective disease-modifying therapies remain scarce. Here, we identify ebselen (EBS) as a promising therapeutic candidate through a phenotypic drug screen in a yeast model of Barth syndrome, a cardiomyopathy caused by defective cardiolipin maturation. EBS improved oxidative phosphorylation-dependent growth across diverse fungal models of mitochondrial diseases, including defects in complex I, complex IV, mitochondrial DNA maintenance, mitochondrial translation, and ATP synthase. Therapeutic efficacy was further validated in patient-derived fibroblasts, iPSC-derived cardiomyocytes, and a cardiolipin-deficient mouse model. Mechanistically, EBS acts independently of its established antioxidant activity by engaging a conserved metabolic program that suppresses cytosolic translation while stimulating pyruvate dehydrogenase-dependent tricarboxylic acid cycle activity, thereby improving proteostasis and mitochondrial bioenergetic function. These effects are likely coordinated through lysosome-associated mTOR signaling, consistent with the localization of EBS to lysosomes and its colocalization with mTOR. Together, our findings identify a conserved mechanism for enhancing mitochondrial function and establish ebselen as a strong candidate for therapeutic repurposing in Barth syndrome and a broad spectrum of inherited mitochondrial disorders.

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Publication Details

Journal
EMBO Molecular Medicine
Published
2026-10-05
DOI
https://doi.org/10.1038/s44321-026-00518-1
Primary Topic
Mitochondrial Function and Pathology
Type
article
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article

Ebselen restores mitochondrial function through metabolic rewiring in Barth syndrome and related mitochondrial diseases

Valérie Desquiret‐Dumas, Nathalie Bonnefoy, Caroline Tokarski, Laurent Monassier et al.
EMBO Molecular Medicine
Mitochondrial Function and Pathology
article

Ebselen restores mitochondrial function through metabolic rewiring in Barth syndrome and related mitochondrial diseases

Valérie Desquiret‐Dumas, Nathalie Bonnefoy, Caroline Tokarski, Laurent Monassier, Yeranuhi Hovhannisyan, Vincent Procaccio, Marc-Alexandre D’Elia, Naïg Guéguen, Laetitia Dard, Corinne Blancard, Anaïs Hoarau, Claire Almyre, Jordan Rivron, Olivier R. Baris, Juliette Jouhet, Yaser Hashem, Déborah Tribouillard‐Tanvier, Cyrille Guimaraes, Jean‐Paul di Rago, Alexandre Favereaux, Julie Martineau, Aurélie Massoni‐Laporte, Cécile Duplàa, Stéphane Claverol, Mélody Dufossée, Jean‐François Dumas, Carole H. Sellem, Douglas Strathdee, Pierre Costet, Estelle Ayme‐Dietrich, Onnik Agbulut, François Godard, Bénédicte Salin, Jim Dompierre, Marie‐Alix Derieppe, Stéphane Azoulay, Vanessa Bergeron, Jeremy Richard, Nolwenn Bounaix, Anne-Louise Cayer, Camille Charles
article en

Abstract

Abstract Despite major advances in the genetic diagnosis of mitochondrial disorders, effective disease-modifying therapies remain scarce. Here, we identify ebselen (EBS) as a promising therapeutic candidate through a phenotypic drug screen in a yeast model of Barth syndrome, a cardiomyopathy caused by defective cardiolipin maturation. EBS improved oxidative phosphorylation-dependent growth across diverse fungal models of mitochondrial diseases, including defects in complex I, complex IV, mitochondrial DNA maintenance, mitochondrial translation, and ATP synthase. Therapeutic efficacy was further validated in patient-derived fibroblasts, iPSC-derived cardiomyocytes, and a cardiolipin-deficient mouse model. Mechanistically, EBS acts independently of its established antioxidant activity by engaging a conserved metabolic program that suppresses cytosolic translation while stimulating pyruvate dehydrogenase-dependent tricarboxylic acid cycle activity, thereby improving proteostasis and mitochondrial bioenergetic function. These effects are likely coordinated through lysosome-associated mTOR signaling, consistent with the localization of EBS to lysosomes and its colocalization with mTOR. Together, our findings identify a conserved mechanism for enhancing mitochondrial function and establish ebselen as a strong candidate for therapeutic repurposing in Barth syndrome and a broad spectrum of inherited mitochondrial disorders.

EMBO Molecular Medicine
Université de Tours (FR), Centre National de la Recherche Scientifique (FR), Université de Bordeaux (FR), Inserm (FR), Commissariat à l'Énergie Atomique et aux Énergies Alternatives (FR), Université Paris-Saclay (FR), CEA Grenoble (FR), Sorbonne Université (FR), Institut de Chimie de Nice (FR), Institut National de Recherche pour l'Agriculture, l'Alimentation et l'Environnement (FR), Services déconcentrés d'appui à la recherche Nouvelle-Aquitaine-Bordeaux (FR), Laboratoire Physiologie Cellulaire & Végétale (FR), Institut de Biologie Paris-Seine (FR), CEA Paris-Saclay (FR), Institut Interdisciplinaire de Neuroscience (FR), Institut de Biochimie et Génétique Cellulaires (FR), Cancer Research UK Scotland Institute (GB), Laboratoire de pharmacologie et de toxicologie neurocardiovasculaire (FR), Université d'Angers (FR), Université de Strasbourg (FR), Université Grenoble Alpes (FR)
Openalex Percentile: Top 21%
Mitochondrial Function and Pathology
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