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.

中文翻译：

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巴斯综合征敲入小鼠模型中从脂肪酸氧化到糖酵解的代谢转变

线粒体是细胞代谢和能量供应的中心。巴特综合征 (BTHS) 是一种严重的疾病，由线粒体心磷脂酰基转移酶 tafazzin 功能障碍所致。心磷脂重塑的改变会影响线粒体内膜组织和膜蛋白的功能，例如转运蛋白和氧化磷酸化 (OXPHOS) 系统。在这里，我们描述了一个在tafazzin中携带G197V交换的小鼠模型，对应于BTHS患者。TAZ ^G197V小鼠重现了疾病特异性病理学，包括心脏功能障碍和氧化磷酸化减少。我们发现，由于肉碱棕榈酰转移酶水平降低，突变线粒体表现出脂肪酸驱动的氧化磷酸化缺陷。在小鼠心脏和患者 iPSC 细胞衍生的心肌细胞中，ATP 产生从 OXPHOS 到糖酵解的代谢转换很明显。糖酵解 ATP 产量的增加会使 AMPK 失活，从而导致 TAZ ^G197V代谢信号发生改变。用 AMPK 激活剂处理突变细胞可重建脂肪酸驱动的 OXPHOS，并保护小鼠免受心脏功能障碍的影响。