Activation of the integrated stress response rewires cardiac metabolism in Barth syndrome
Barth Syndrome (BTHS) is an inherited cardiomyopathy caused by defects in the mitochondrial transacylase TAFAZZIN (Taz), required for the synthesis of the phospholipid cardiolipin. BTHS is characterized by heart failure, increased propensity for arrhythmias and a blunted inotropic reserve. Defects in Ca2+-induced Krebs cycle activation contribute to these functional defects, but despite oxidation of pyridine nucleotides, no oxidative stress developed in the heart. Here, we investigated how retrograde signaling pathways orchestrate metabolic rewiring to compensate for mitochondrial defects. In mice with an inducible knockdown (KD) of TAFAZZIN, mitochondrial uptake and oxidation of fatty acids was strongly decreased, while glucose uptake was increased. Unbiased transcriptomic analyses revealed that the activation of the eIF2?/ATF4 axis of the integrated stress response upregulates one-carbon metabolism, which diverts glycolytic intermediates towards the biosynthesis of serine and fuels the biosynthesis of glutathione. In addition, strong upregulation of the glutamate/cystine antiporter xCT increases cardiac cystine import required for glutathione synthesis. Increased glutamate uptake facilitates anaplerotic replenishment of the Krebs cycle, sustaining energy production and antioxidative pathways. These data indicate that ATF4-driven rewiring of metabolism compensates for defects in mitochondrial uptake of fatty acids to sustain energy production and antioxidation. Overall design: Heart tissue and skeletal muscle from a mouse model with a systemic reduction of Tafazzin (Taz) gene expression at an age of 20 weeks are compared to control. Deficiency in Taz gene expression causes mitochondrial dysfunction and cardiomyopathy and relates to Barth syndrome (BTHS). To profile the whole transcriptome expression changes between Taz-KD and WT mice,  Illumina PE RNA-seq were performed using total RNAs extracted from cardiac tissue and skelecal muscle of Taz-KD and WT mice. 10 cardiac tissue are from WT and Taz-KD mice; 10 skeletal muscle from WT and Taz-KD mice.