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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BibTeX
@article{almyre2026ebselen,
title = {{Ebselen restores mitochondrial function through metabolic rewiring in Barth syndrome and related mitochondrial diseases}},
author = {Claire Almyre and Anne-Louise Cayer and Nolwenn Bounaix and Anaïs Hoarau and Marie-Alix Derieppe and Julie Martineau and Pierre Costet and Camille Charles and Mélody Dufossée and Cécile Duplaa and Jim Dompierre and Bénédicte Salin and Marc-Alexandre D’elia and Corinne Blancard and Aurélie Massoni-Laporte and Stéphane Claverol and Caroline Tokarski and Yaser Hashem and Alexandre Favereaux and Yeranuhi Hovhannisyan and Juliette Jouhet and Cyrille Guimaraes and Jean-François Dumas and Olivier Baris and Laetitia Dard and Jérémy Richard and Vanessa Bergeron and Naïg Gueguen and Valérie Desquiret-Dumas and Jordan Rivron and Douglas Strathdee and Carole Sellem and Nathalie Bonnefoy and Laurent Monassier and Estelle Ayme-Dietrich and Onnik Agbulut and Stéphane Azoulay and Jean-Paul Di Rago and Vincent Procaccio and François Godard and Déborah Tribouillard-Tanvier},
journal = {EMBO Molecular Medicine},
year = {2026},
month = oct,
doi = {10.1038/s44321-026-00518-1},
url = {https://hal.science/hal-05798812v1},
note = {CC BY},
}
RIS
TY - JOUR
TI - Ebselen restores mitochondrial function through metabolic rewiring in Barth syndrome and related mitochondrial diseases
AU - Claire Almyre
AU - Anne-Louise Cayer
AU - Nolwenn Bounaix
AU - Anaïs Hoarau
AU - Marie-Alix Derieppe
AU - Julie Martineau
AU - Pierre Costet
AU - Camille Charles
AU - Mélody Dufossée
AU - Cécile Duplaa
AU - Jim Dompierre
AU - Bénédicte Salin
AU - Marc-Alexandre D’elia
AU - Corinne Blancard
AU - Aurélie Massoni-Laporte
AU - Stéphane Claverol
AU - Caroline Tokarski
AU - Yaser Hashem
AU - Alexandre Favereaux
AU - Yeranuhi Hovhannisyan
AU - Juliette Jouhet
AU - Cyrille Guimaraes
AU - Jean-François Dumas
AU - Olivier Baris
AU - Laetitia Dard
AU - Jérémy Richard
AU - Vanessa Bergeron
AU - Naïg Gueguen
AU - Valérie Desquiret-Dumas
AU - Jordan Rivron
AU - Douglas Strathdee
AU - Carole Sellem
AU - Nathalie Bonnefoy
AU - Laurent Monassier
AU - Estelle Ayme-Dietrich
AU - Onnik Agbulut
AU - Stéphane Azoulay
AU - Jean-Paul Di Rago
AU - Vincent Procaccio
AU - François Godard
AU - Déborah Tribouillard-Tanvier
PY - 2026
DA - 2026/10/05
JO - EMBO Molecular Medicine
DO - 10.1038/s44321-026-00518-1
UR - https://hal.science/hal-05798812v1
AB - 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.
SN - 1757-4676
SN - 1757-4684
ER -