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. TAZG197V 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 TAZG197V . Treatment of mutant cells with AMPK activator reestablishes fatty acid-driven OXPHOS and protects mice against cardiac dysfunction.

Cluster of Excellence Multiscale Bioimaging from Molecular Machines to Networks of Excitable Cells University of Göttingen Göttingen Germany

Czech Centre for Phenogenomics Institute of Molecular Genetics of the CAS Prague Czech Republic

Department for Epigenetics and Systems Medicine in Neurodegenerative Diseases German Center for Neurodegenerative Diseases Göttingen Germany

Department of Cardiovascular Physiology University Medical Center Göttingen Göttingen Germany

Department of Cellular Biochemistry University Medical Center Göttingen Göttingen Germany

Department of Psychiatry and Psychotherapy University Medical Center Göttingen Göttingen Germany

DZHK partner site Göttingen Göttingen Germany

Heidelberg University Biochemistry Center Heidelberg Germany

Institute for Clinical Chemistry University Medical Center Göttingen Göttingen Germany

Max Planck Institute for Multidisciplinary Science Göttingen Germany

Stem Cell Unit Clinic for Cardiology and Pneumology University Medical Center Göttingen Georg August University Göttingen Göttingen Germany

The Bioanalytical Mass Spectrometry Group Max Planck Institute for Multidisciplinary Sciences Göttingen Germany

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