PITX2 deficiency leads to atrial mitochondrial dysfunction

作者：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, Lluı́s Mont, Stéphane 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 · 发表于：Cardiovascular Research · 年份：2024 · DOI：10.1093/cvr/cvae169 · 被引用次数：30 · 研究领域：Congenital heart defects research、Wnt/β-catenin signaling in development and cancer、Cardiac Fibrosis and Remodeling

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 conf...