PITX2 deficiency leads to atrial mitochondrial dysfunction, 2024, Reyat et al (atrial fibrillation)

Paper from Dec 2024.

PITX2 deficiency leads to atrial mitochondrial dysfunction
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

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.

Web | PDF | Cardiovascular Research | Open Access
 
You must log in or register to reply here.
Back
Top Bottom