2. Academic Validation
  3. Metabolic switch from fatty acid oxidation to glycolysis in knock-in mouse model of Barth syndrome

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

  • EMBO Mol Med. 2023 Aug 3;e17399. doi: 10.15252/emmm.202317399.
Arpita Chowdhury # 1,  Angela Boshnakovska # 1,  Abhishek Aich 1 2,  Aditi Methi 3 4,  Ana Maria Vergel Leon 5,  Ivan Silbern 6 7,  Christian Lüchtenborg 8,  Lukas Cyganek 2 9 10,  Jan Prochazka 11,  Radislav Sedlacek 11,  Jiri Lindovsky 11,  Dominic Wachs 1,  Zuzana Nichtova 11,  Dagmar Zudova 11,  Gizela Koubkova 11,  André Fischer 2 3 4,  Henning Urlaub 6 7,  Britta Brügger 8,  Dörthe M Katschinski 5,  Jan Dudek 1,  Peter Rehling 1 2 12
Affiliations

Affiliations

  • 1 Department of Cellular Biochemistry, University Medical Center Göttingen, Göttingen, Germany.
  • 2 Cluster of Excellence "Multiscale Bioimaging: from Molecular Machines to Networks of Excitable Cells" (MBExC), University of Göttingen, Göttingen, Germany.
  • 3 Department of Psychiatry and Psychotherapy, University Medical Center Göttingen, Göttingen, Germany.
  • 4 Department for Epigenetics and Systems Medicine in Neurodegenerative Diseases, German Center for Neurodegenerative Diseases (DZNE), Göttingen, Germany.
  • 5 Department of Cardiovascular Physiology, University Medical Center Göttingen, Göttingen, Germany.
  • 6 The Bioanalytical Mass Spectrometry Group, Max Planck Institute for Multidisciplinary Sciences, Göttingen, Germany.
  • 7 Institute for Clinical Chemistry, University Medical Center Göttingen, Göttingen, Germany.
  • 8 Heidelberg University Biochemistry Center (BZH), Heidelberg, Germany.
  • 9 DZHK (German Center for Cardiovascular Research) partner site Göttingen, Göttingen, Germany.
  • 10 Stem Cell Unit, Clinic for Cardiology and Pneumology, University Medical Center Göttingen, Georg-August University Göttingen, Göttingen, Germany.
  • 11 Czech Centre for Phenogenomics, Institute of Molecular Genetics of the CAS, Prague, Czech Republic.
  • 12 Max Planck Institute for Multidisciplinary Science, Göttingen, Germany.
  • # Contributed equally.
PMID: 37533404 DOI: 10.15252/emmm.202317399
Abstract

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.

Keywords

Barth syndrome; cardiolipin; cardiomyopathy; mitochondria; tafazzin.

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