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. 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. © 2023 The Authors. Published under the terms of the CC BY 4.0 license.

Authors Chowdhury A, Boshnakovska A, Aich A, Methi A, Vergel Leon AM, Silbern I, Lüchtenborg C, Cyganek L, Prochazka J, Sedlacek R, Lindovsky J, Wachs D, Nichtova Z, Zudova D, Koubkova G, Fischer A, Urlaub H, Brügger B, Katschinski DM, Dudek J, Rehling P
Journal EMBO molecular medicine
Publication Date 2023 Sep 11;15(9):e17399
PubMed 37533404
PubMed Central PMC10493589
DOI 10.15252/emmm.202317399

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