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

0576227 - ÚMG 2024 RIV US eng J - Journal Article
Chowdhury, A. - Boshnakovska, A. - Aich, A. - Methi, A. - Leon, A. M. V. - Silbern, I. - Luechtenborg, C. - Cyganek, L. - Procházka, Jan - Sedláček, Radislav - Lindovský, Jiří - Wachs, D. - Nichtová, Zuzana - Zudová, Dagmar - Koubková, Gizela - Fischer, A. - Urlaub, H. - Bruegger, B. - Katschinski, D. M. - Dudek, J. - Rehling, P.
Metabolic switch from fatty acid oxidation to glycolysis in knock-in mouse model of Barth syndrome.
EMBO Molecular Medicine. Roč. 15, č. 9 (2023), č. článku e17399. ISSN 1757-4676. E-ISSN 1757-4684
R&D Projects: GA MŠMT(CZ) LM2018126; GA MŠMT LM2023036; GA MŠMT EF18_046/0015861
Institutional support: RVO:68378050
Keywords : Barth syndrome * cardiolipin * cardiomyopathy * mitochondria * tafazzin
OECD category: Biochemistry and molecular biology
Impact factor: 11.1, year: 2022
Method of publishing: Open access
https://www.embopress.org/doi/full/10.15252/emmm.202317399

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.
Permanent Link: https://hdl.handle.net/11104/0346207