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.