Metabolic switch from fatty acid oxidation to glycolysis in knock‐in mouse model of Barth syndrome
Year: 2023
Type: article
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.
Source: EMBO Molecular Medicine
Authors: Arpita Chowdhury, Angela Boshnakovska, Abhishek Aich, Aditi Methi, Ana Maria Vergel Leon, Ivan Silbern, Christian Lüchtenborg, Lukas Cyganek, Jan Prochazka, Radislav Sedlacek, Jiri Lindovsky, Dominic Wachs, Zuzana Nichtova, Dagmar Zudova, Gizela Koubkova, André Fischer, Henning Urlaub, Britta Brügger, Dörthe M Katschinski, Jan Dudek, Peter Rehling
Institutions: Universitätsmedizin Göttingen, Multiscale Bioimaging, University of Göttingen, German Center for Neurodegenerative Diseases, Max Planck Institute for Multidisciplinary Sciences, Heidelberg University, German Centre for Cardiovascular Research, Czech Academy of Sciences, Czech Academy of Sciences, Institute of Molecular Genetics, Czech Centre for Phenogenomics
Language: English
Subfield: Molecular Biology
Domain: Life Sciences
Open Access status: gold
Estimated APC paid: $5,338
Awards: G1156537739, G1232952689, G1436661812, G1692958442, G1751328538, G1906785337, G2092439215, G2590009325, G2828991432, G3130636412, G3445732291, Czech Centre for Phenogenomics, Czech Centre for Phenogenomics, G4195383042, G4724125240, G4783087731, TRR 83: Molekulare Architektur und zelluläre Funktionen von Lipid/Protein Komplexen, G5080845649, G5097284512, G5131877326, G5197873167, G5222967801, G5511180595, G5641063287, G584537252, G5957677470, EXC 2067: Multiscale Bioimaging: Von molekularen Maschinen zu Netzwerken erregbarer Zellen, G6461157608, G709394430, G7254253043, G7843559024, G7987891391, G800271517
OpenAlex ID: W4385514478