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

Chowdhury, A., Boshnakovska, A., Aich, A., Methi, A., Vergel Leon, A. M., Silbern, I., et al. (2023). Metabolic switch from fatty acid oxidation to glycolysis in knock-in mouse model of Barth syndrome. Embo Molecular Medicine, 15(9): e17399. doi:10.15252/emmm.202317399.

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Item Permalink: https://hdl.handle.net/21.11116/0000-000D-BEED-3 Version Permalink: https://hdl.handle.net/21.11116/0000-000D-BEEE-2
Genre: Journal Article

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EMBO Mol Med - 2023 - Chowdhury.pdf (Publisher version), 4MB
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EMBO Mol Med - 2023 - Chowdhury.pdf
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 Creators:
Chowdhury, Arpita, Author
Boshnakovska, Angela, Author
Aich, Abhishek, Author
Methi, Aditi, Author
Vergel Leon, Ana Maria , Author
Silbern, Ivan1, Author           
Lüchtenborg, Christian, Author
Cyganek, Lukas, Author
Prochazka, Jan, Author
Sedlacek, Radislav, Author
Lindovsky, Jiri, Author
Wachs, Dominic, Author
Nichtova, Zuzana, Author
Zudova, Dagmar, Author
Koubkova, Gizela, Author
Fischer, André, Author
Urlaub, Henning1, Author           
Brügger, Britta, Author
Katschinski, Dörthe M., Author
Dudek, Jan, Author
Rehling, Peter2, Author            more..
Affiliations:
1Research Group of Bioanalytical Mass Spectrometry, Max Planck Institute for Multidisciplinary Sciences, Max Planck Society, ou_3350290              
2MPI-NAT Fellow Mitochondrial Biogenesis and Assembly of membrane Protein Complexes, Max Planck Institute for Multidisciplinary Sciences, Max Planck Society, ou_3505610              

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 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 TAZGG197V. Treatment of mutant cells with AMPK activator reestablishes fatty acid-driven OXPHOS and protects mice against cardiac dysfunction.

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Language(s): eng - English
 Dates: 2023-08-032023-09-11
 Publication Status: Issued
 Pages: -
 Publishing info: -
 Table of Contents: -
 Rev. Type: Peer
 Identifiers: DOI: 10.15252/emmm.202317399
 Degree: -

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Project name : Supported by the Deutsche Forschungsgemeinschaft under Germany's Excellence Strategy EXC 2067/1-390729940; SFB1002 (A06, PR; D04, AF; S01, LC), SFB1286 (A6/A10, PR & HU), DFG Ka1269/13-1 (DMK), GRK2824 (DMK) and Max Planck Society (PR). JD is supported by the German Research Foundation (DFG; DU1839/2-1).The authors used services of the Czech Centre for Phenogenomics at the Institute of Molecular Genetics supported by the Czech Academy of Sciences RVO 68378050 and by the project LM2018126, LM2023036 Czech Centre for Phenogenomics provided by the Ministry of Education, Youth and Sports of the Czech Republic and by the project CZ.02.1.01/0.0/0.0/18_046/0015861 CCP Infrastructure Upgrade II by MEYS and ESIF. The authors gratefully acknowledge the data storage service SDS@hd supported by the Ministry of Science, Research, and the Arts Baden-Württemberg (MWK) and the DFG through grant INST 35/1314-1 FUGG and INST 35/1503-1 FUGG. Plus, Funding BB: Project-ID 112927078 – Transregio TRR83, project 01. Open Access funding enabled and organized by Projekt DEAL.
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Title: Embo Molecular Medicine
  Abbreviation : Embo Mol. Med.
Source Genre: Journal
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Publ. Info: Chichester : Wiley-Blackwell
Pages: - Volume / Issue: 15 (9) Sequence Number: e17399 Start / End Page: - Identifier: ISSN: 1757-4676
CoNE: https://pure.mpg.de/cone/journals/resource/1757-4676