Metabolic switch from fatty acid oxidation to glycolysis in knock-in mouse model of Barth syndrome.
Arpita ChowdhuryAngela BoshnakovskaAbhishek AichAditi MethiAna Maria Vergel LeonIvan SilbernChristian LüchtenborgLukas CyganekJan ProchazkaRadislav SedlacekJiri LindovskyDominic WachsZuzana NichtovaDagmar ZudovaGizela KoubkovaAndré FischerHenning UrlaubBritta BrüggerDörthe Magdalena KatschinskiJan DudekPeter RehlingPublished in: EMBO molecular medicine (2023)
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.
Keyphrases
- fatty acid
- mouse model
- oxidative stress
- protein kinase
- induced apoptosis
- case report
- wild type
- end stage renal disease
- cell death
- ejection fraction
- left ventricular
- high fat diet induced
- skeletal muscle
- newly diagnosed
- heart failure
- chronic kidney disease
- cell cycle arrest
- reactive oxygen species
- prognostic factors
- endoplasmic reticulum
- magnetic resonance imaging
- peritoneal dialysis
- type diabetes
- nitric oxide
- atrial fibrillation
- magnetic resonance
- metabolic syndrome
- cell proliferation
- adipose tissue
- combination therapy