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

2023 | journal article. A publication with affiliation to the University of Göttingen.

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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. & Lüchtenborg, C. et al.​ (2023) 
EMBO Molecular Medicine, art. e17399​.​ DOI: https://doi.org/10.15252/emmm.202317399 

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Authors
Chowdhury, Arpita; Boshnakovska, Angela; Aich, Abhishek; Methi, Aditi; Vergel Leon, Ana Maria; Silbern, Ivan; Lüchtenborg, Christian; Cyganek, Lukas; Prochazka, Jan; Sedlacek, Radislav; Rehling, Peter 
Abstract
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. 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.
Synopsis image Defective cardiolipin remodeling due to mutation in tafazzin, causes Barth syndrome (BTHS) with cardiac impairment and reduced oxidative phosphorylation. Dysfunctional FAO‐driven OXPHOS due to altered AMPK signaling is restored in BTHS models by treatment with AMPK activator. The characteristic pathology observed in Barth syndrome patients is mirrored by TAZG197V mice, which are characterized by severe cardiac dysfunction and reduced oxidative phosphorylation. A switch in the metabolic pathways from oxidative phosphorylation to glycolysis for compensating ATP production is evident in TAZG197V mutants. Due to metabolic shift and increased ATP, AMPK pathway is shut down affecting transcription of CPTs with reduced fatty acid oxidation, a known consequence of heart failure. Functional restoration of cardiac function in TAZG197V mice is reestablished by treating mutant mice with an AMPK activator, which restores fatty acid‐driven oxidative phosphorylation in the heart.
Issue Date
2023
Journal
EMBO Molecular Medicine 
Project
EXC 2067: Multiscale Bioimaging 
SFB 1002: Modulatorische Einheiten bei Herzinsuffizienz 
SFB 1002 | A06: Molekulare Grundlagen mitochondrialer Kardiomyopathien 
SFB 1002 | D04: Bedeutung der Methylierung von RNA (m6A) und des Histons H3 (H3K4) in der Herzinsuffizienz 
SFB 1002 | S01: In vivo und in vitro Krankheitsmodelle 
SFB 1286: Quantitative Synaptologie 
SFB 1286 | A06: Mitochondrienfunktion und -umsatz in Synapsen 
Working Group
RG Cyganek (Stem Cell Unit) 
RG A. Fischer (Epigenetics and Systems Medicine in Neurodegenerative Diseases) 
RG Urlaub (Bioanalytische Massenspektrometrie) 
RG Rehling (Mitochondrial Protein Biogenesis) 
External URL
https://mbexc.uni-goettingen.de/literature/publications/738
https://sfb1002.med.uni-goettingen.de/production/literature/publications/481
https://sfb1286.uni-goettingen.de/literature/publications/215
ISSN
1757-4676
eISSN
1757-4684
Language
English
Sponsor
Open-Access-Publikationsfonds 2023

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