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, and in induced pluripotent stem cell-derived cardiac myocytes, mitochondrial uptake and oxidation of fatty acids was strongly decreased, while glucose uptake was increased. Unbiased transcriptomic analyses revealed that the activation of the eIF2α/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.

巴特综合征 (BTHS) 是一种遗传性心肌病，由合成磷脂心磷脂所需的线粒体转酰基酶 TAFAZZIN ( Taz ) 缺陷引起。 BTHS 的特点是心力衰竭、心律失常倾向增加和正性肌力储备减弱。 Ca ²⁺诱导的克雷布斯循环激活的缺陷导致这些功能缺陷，但尽管吡啶核苷酸被氧化，但心脏中并未产生氧化应激。在这里，我们研究了逆行信号通路如何协调代谢重连以补偿线粒体缺陷。在 TAFAZZIN 诱导敲低（KD）小鼠和诱导多能干细胞来源的心肌细胞中，线粒体摄取和脂肪酸氧化强烈减少，而葡萄糖摄取增加。无偏转录组分析表明，整合应激反应的 eIF2α/ATF4 轴的激活上调一碳代谢，从而将糖酵解中间体转向丝氨酸的生物合成，并促进谷胱甘肽的生物合成。此外，谷氨酸/胱氨酸逆向转运蛋白 xCT 的强烈上调会增加谷胱甘肽合成所需的心脏胱氨酸输入。谷氨酸吸收的增加有助于三羧酸循环的回补补充，维持能量产生和抗氧化途径。这些数据表明，ATF4 驱动的代谢重新布线可补偿线粒体摄取脂肪酸的缺陷，以维持能量产生和抗氧化。