Metabolic switch from fatty acid oxidation to glycolysis in knock‐in mouse model of Barth syndrome

Mitochondria are central for cellular metabolism and energy supply. Barth syndrome (BTHS) is a severe disorder, due to dysfunction of the mitochondrial cardiolipin acyl transferase tafazzin. Altered cardiolipin remodeling affects mitochondrial inner membrane organization and function of membrane proteins such as transporters and the oxidative phosphorylation (OXPHOS) system. Here, we describe a mouse model that carries a G197V exchange in tafazzin, corresponding to BTHS patients. TAZ G197V mice recapitulate disease‐specific pathology including cardiac dysfunction and reduced oxidative phosphorylation. We show that mutant mitochondria display defective fatty acid‐driven oxidative phosphorylation due to reduced levels of carnitine palmitoyl transferases. A metabolic switch in ATP production from OXPHOS to glycolysis is apparent in mouse heart and patient iPSC cell‐derived cardiomyocytes. An increase in glycolytic ATP production inactivates AMPK causing altered metabolic signaling in TAZ G197V . Treatment of mutant cells with AMPK activator reestablishes fatty acid‐driven OXPHOS and protects mice against cardiac dysfunction. Synopsis Defective cardiolipin remodeling due to mutation in tafazzin, causes Barth syndrome (BTHS) with cardiac impairment and reduced oxidative phosphorylation. Dysfunctional FAO‐driven OXPHOS due to altered AMPK signaling is restored in BTHS models by treatment with AMPK activator. The characteristic pathology observed in Barth syndrome patients is mirrored by TAZG197V mice, which are characterized by severe cardiac dysfunction and reduced oxidative phosphorylation. A switch in the metabolic pathways from oxidative phosphorylation to glycolysis for compensating ATP production is evident in TAZG197V mutants. Due to metabolic shift and increased ATP, AMPK pathway is shut down affecting transcription of CPTs with reduced fatty acid oxidation, a known consequence of heart failure. Functional restoration of cardiac function in TAZG197V mice is reestablished by treating mutant mice with an AMPK activator, which restores fatty acid‐driven oxidative phosphorylation in the heart. Graphical Abstract Defective cardiolipin remodeling due to mutation in tafazzin causes Barth syndrome (BTHS) with cardiac impairment and reduced oxidative phosphorylation. Dysfunctional FAO‐driven OXPHOS due to altered AMPK signaling is restored in BTHS models by treatment with AMPK activator.