PITX2缺乏导致心房线粒体功能障碍。
PITX2 deficiency leads to atrial mitochondrial dysfunction.
作者信息
Reyat Jasmeet S, Sommerfeld Laura C, O'Reilly Molly, Roth Cardoso Victor, Thiemann Ellen, Khan Abdullah O, O'Shea Christopher, Harder Sönke, Müller Christian, Barlow Jonathan, Stapley Rachel J, Chua Winnie, Kabir S Nashitha, Grech Olivia, Hummel Oliver, Hübner Norbert, Kääb Stefan, Mont Lluis, Hatem Stéphane N, Winters Joris, Zeemering Stef, Morgan Neil V, Rayes Julie, Gehmlich Katja, Stoll Monika, Brand Theresa, Schweizer Michaela, Piasecki Angelika, Schotten Ulrich, Gkoutos Georgios V, Lorenz Kristina, Cuello Friederike, Kirchhof Paulus, Fabritz Larissa
机构信息
Institute of Cardiovascular Sciences, College of Medical and Dental Sciences, University of Birmingham, Wolfson Drive, B15 2TT Birmingham, UK.
Division of Cardiovascular Medicine, Radcliffe Department of Medicine, University of Oxford, John Radcliffe Hospital, OX3 9DU Oxford, UK.
出版信息
Cardiovasc Res. 2024 Dec 4;120(15):1907-1923. doi: 10.1093/cvr/cvae169.
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.
目的
左心房PITX2表达降低与心房心肌病及心房颤动（AF）相关。PITX2在成人心脏中仅限于左心房心肌细胞（aCMs）。PITX2缺乏、心房心肌病和AF之间的联系尚未完全明确。
方法与结果
为了确定PITX2缺乏与AF之间的联系机制，我们构建并鉴定了源自人诱导多能干细胞（hiPSC）的PITX2缺陷型人aCMs及其对照。PITX2缺陷型hiPSC衍生的心房心肌细胞显示肌节缩短且排列紊乱，单核化增加。电子显微镜检查发现，与同基因对照相比，线粒体数量增加且体积变小。PITX2缺陷型hiPSC衍生的心房心肌细胞中线粒体蛋白表达发生改变。单核RNA测序发现，PITX2缺陷型hiPSC衍生的心房心肌细胞在细胞呼吸途径以及线粒体和离子通道基因的差异表达方面存在差异。在hiPSC衍生的心房心肌细胞中抑制PITX2可重现细胞呼吸失调。PITX2缺陷型hiPSC衍生的心房心肌细胞中线粒体呼吸转变为糖酵解增加。PITX2缺陷型人hiPSC衍生的心房心肌细胞显示出自发搏动率更高。动作电位时程变异性更大，早期复极化总体延长，这与代谢缺陷一致。基因表达分析证实，与43例窦性心律患者相比，42例AF患者左心房线粒体基因发生了变化。人左心房中线粒体（COX7C）和代谢（FOXO1）基因的失调与PITX2表达相关。
结论
PITX2缺乏导致人aCMs中心房线粒体功能障碍以及代谢转变为糖酵解。PITX2依赖的代谢变化可能导致PITX2缺陷型心房出现结构和功能缺陷。
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