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Metabolic switch from fatty acid oxidation to glycolysis in knock-in mouse model of Barth syndrome
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SYSNO ASEP 0576227 Document Type J - Journal Article R&D Document Type Journal Article Subsidiary J Článek ve WOS Title Metabolic switch from fatty acid oxidation to glycolysis in knock-in mouse model of Barth syndrome Author(s) Chowdhury, A. (DE)
Boshnakovska, A. (DE)
Aich, A. (DE)
Methi, A. (DE)
Leon, A. M. V. (DE)
Silbern, I. (DE)
Luechtenborg, C. (DE)
Cyganek, L. (DE)
Procházka, Jan (UMG-J) ORCID
Sedláček, Radislav (UMG-J) RID
Lindovský, Jiří (UMG-J) ORCID
Wachs, D. (DE)
Nichtová, Zuzana (UMG-J)
Zudová, Dagmar (UMG-J)
Koubková, Gizela (UMG-J)
Fischer, A. (DE)
Urlaub, H. (DE)
Bruegger, B. (DE)
Katschinski, D. M. (DE)
Dudek, J. (DE)
Rehling, P. (DE)Number of authors 21 Article number e17399 Source Title EMBO Molecular Medicine. - : Wiley - ISSN 1757-4676
Roč. 15, č. 9 (2023)Number of pages 21 s. Language eng - English Country US - United States Keywords Barth syndrome ; cardiolipin ; cardiomyopathy ; mitochondria ; tafazzin OECD category Biochemistry and molecular biology R&D Projects LM2018126 GA MŠMT - Ministry of Education, Youth and Sports (MEYS) LM2023036 GA MŠMT - Ministry of Education, Youth and Sports (MEYS) EF18_046/0015861 GA MŠMT - Ministry of Education, Youth and Sports (MEYS) Method of publishing Open access Institutional support UMG-J - RVO:68378050 UT WOS 001041495700001 EID SCOPUS 85166675912 DOI 10.15252/emmm.202317399 Annotation 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. Workplace Institute of Molecular Genetics Contact Nikol Škňouřilová, nikol.sknourilova@img.cas.cz, Tel.: 241 063 217 Year of Publishing 2024 Electronic address https://www.embopress.org/doi/full/10.15252/emmm.202317399
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