MassIVE MSV000092116

Partial Public PXD042788

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

Description

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 patient. 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 failure. [doi:10.25345/C50R9MD9P] [dataset license: CC0 1.0 Universal (CC0 1.0)]

Keywords: Barth Syndrome, Mus musculus, Fatty acid oxidation

Contact

Principal Investigators:
(in alphabetical order)
Peter Rehling, Department of Cellular Biochemistry, University Medical Center Goettingen, 37073 Goettingen, Germany, Germany
Submitting User: Svenja_Kaufmann_1
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