Aims Reduced left atrial PITX2 is associated with atrial cardiomyopathy and atrial fibrillation (AF). PITX2 is restricted to left atrial cardiomyocytes (aCMs) in the adult heart. The links between PITX2 deficiency, atrial cardiomyopathy, and AF are not fully understood. Methods and results To identify mechanisms linking PITX2 deficiency to AF, we generated and characterized PITX2-deficient human aCMs derived from human induced pluripotent stem cells (hiPSC) and their controls. PITX2-deficient hiPSC-derived atrial cardiomyocytes showed shorter and disorganized sarcomeres and increased mononucleation. Electron microscopy found an increased number of smaller mitochondria compared with isogenic controls. Mitochondrial protein expression was altered in PITX2-deficient hiPSC-derived atrial cardiomyocytes. Single-nuclear RNA-sequencing found differences in cellular respiration pathways and differentially expressed mitochondrial and ion channel genes in PITX2-deficient hiPSC-derived atrial cardiomyocytes. PITX2 repression in hiPSC-derived atrial cardiomyocytes replicated dysregulation of cellular respiration. Mitochondrial respiration was shifted to increased glycolysis in PITX2-deficient hiPSC-derived atrial cardiomyocytes. PITX2-deficient human hiPSC-derived atrial cardiomyocytes showed higher spontaneous beating rates. Action potential duration was more variable with an overall prolongation of early repolarization, consistent with metabolic defects. Gene expression analyses confirmed changes in mitochondrial genes in left atria from 42 patients with AF compared with 43 patients with sinus rhythm. Dysregulation of left atrial mitochondrial (COX7C) and metabolic (FOXO1) genes was associated with PITX2 expression in human left atria. Conclusion PITX2 deficiency causes atrial mitochondrial dysfunction and a metabolic shift to glycolysis in human aCMs. PITX2-dependent metabolic changes can contribute to the structural and functional defects found in PITX2-deficient atria.

中文翻译：

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PITX2 缺陷导致心房线粒体功能障碍


目的 减少左心房 PITX2 与房性心肌病和心房颤动 （AF） 有关。PITX2 仅限于成人心脏的左心房心肌细胞 （aCM）。PITX2 缺乏症、心房心肌病和 AF 之间的联系尚不完全清楚。方法和结果 为了确定 PITX2 缺陷与 AF 相关的机制，我们生成并表征了源自人诱导多能干细胞 （hiPSC） 及其对照的 PITX2 缺陷型人 aCM。PITX2 缺陷型 hiPSC 来源的心房心肌细胞显示更短且杂乱无章的肌节和增加的单核细胞。电子显微镜发现，与同基因对照相比，较小的线粒体数量增加。PITX2 缺陷型 hiPSC 来源的心房心肌细胞的线粒体蛋白表达发生改变。单核 RNA 测序发现 PITX2 缺陷型 hiPSC 来源的心房心肌细胞中细胞呼吸途径以及线粒体和离子通道基因的差异表达存在差异。hiPSC 来源的心房心肌细胞中的 PITX2 抑制复制了细胞呼吸失调。线粒体呼吸转变为 PITX2 缺陷型 hiPSC 来源的心房心肌细胞的糖酵解增加。PITX2 缺陷的人 hiPSC 来源的心房心肌细胞表现出更高的自发跳动率。动作电位持续时间变化更大，早期复极化的总体延长，与代谢缺陷一致。基因表达分析证实了 42 例 AF 患者与 43 例窦性心律患者相比，左心房线粒体基因的变化。左心房线粒体 （COX7C） 和代谢 （FOXO1） 基因失调与人左心房 PITX2 表达有关。 结论 PITX2 缺陷导致人 aCMs 心房线粒体功能障碍和向糖酵解的代谢转变。PITX2 依赖性代谢变化可导致 PITX2 缺陷型心房的结构和功能缺陷。