PITX2 deficiency leads to atrial mitochondrial dysfunction.

IF 10.2 1区医学 Q1 CARDIAC & CARDIOVASCULAR SYSTEMS

Cardiovascular Research Pub Date : 2024-12-04 DOI:10.1093/cvr/cvae169

Jasmeet S Reyat, Laura C Sommerfeld, Molly O'Reilly, Victor Roth Cardoso, Ellen Thiemann, Abdullah O Khan, Christopher O'Shea, Sönke Harder, Christian Müller, Jonathan Barlow, Rachel J Stapley, Winnie Chua, S Nashitha Kabir, Olivia Grech, Oliver Hummel, Norbert Hübner, Stefan Kääb, Lluis Mont, Stéphane N Hatem, Joris Winters, Stef Zeemering, Neil V Morgan, Julie Rayes, Katja Gehmlich, Monika Stoll, Theresa Brand, Michaela Schweizer, Angelika Piasecki, Ulrich Schotten, Georgios V Gkoutos, Kristina Lorenz, Friederike Cuello, Paulus Kirchhof, Larissa Fabritz

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引用次数: 0

Abstract

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.

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PITX2 缺乏会导致心房线粒体功能障碍。

目的：左心房 PITX2 减少与心房心肌病和心房颤动有关。在成人心脏中，PITX2 仅限于左心房心肌细胞。PITX2缺乏症、心房心肌病和心房颤动之间的联系尚不完全清楚：为了确定 PITX2 缺乏症与心房颤动之间的联系机制，我们生成了 PITX2 缺乏症的人类心房心肌细胞，并对其进行了鉴定，这些细胞来源于人类诱导多能干细胞（hiPSC）及其对照组。PITX2缺陷型hiPSC衍生的心房心肌细胞显示出较短且无序的肌节和较高的单核性。电子显微镜发现，与对照组相比，较小的线粒体数量增加。PITX2缺陷的hiPSC衍生心房心肌细胞的线粒体蛋白表达发生了改变。单核 RNA 测序发现，在 PITX2 基因缺陷的 hiPSC 衍生心房心肌细胞中，细胞呼吸途径和线粒体及离子通道基因的表达存在差异。PITX2 在源自 hiPSC 的心房心肌细胞中的抑制复制了细胞呼吸的失调。在 PITX2 缺失的 hiPSC 衍生心房心肌细胞中，线粒体呼吸转变为糖酵解增加。PITX2缺陷的人类hiPSC衍生心房心肌细胞显示出更高的自发跳动率。动作电位持续时间变化较大，早期复极化时间总体延长，这与代谢缺陷一致。基因表达分析证实，与 43 名窦性心律患者相比，42 名心房颤动患者左心房线粒体基因发生了变化。左心房线粒体（COX7C）和代谢（FOXO1）基因的失调与人类左心房中 PITX2 的表达有关：总之，PITX2 缺乏会导致线粒体功能障碍，并使人心房心肌细胞的代谢转向糖酵解。PITX2 依赖性代谢变化可导致 PITX2 缺乏性心房的结构和功能缺陷。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

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来源期刊

Cardiovascular Research 医学-心血管系统

CiteScore

21.50

自引率

3.70%

发文量

547

审稿时长

1 months

期刊介绍： Cardiovascular Research Journal Overview: International journal of the European Society of Cardiology Focuses on basic and translational research in cardiology and cardiovascular biology Aims to enhance insight into cardiovascular disease mechanisms and innovation prospects Submission Criteria: Welcomes papers covering molecular, sub-cellular, cellular, organ, and organism levels Accepts clinical proof-of-concept and translational studies Manuscripts expected to provide significant contribution to cardiovascular biology and diseases