PITX2 deficiency leads to atrial mitochondrial dysfunction-Reference-Cited by-同舟云学术

PITX2 deficiency leads to atrial mitochondrial dysfunction

Published:2024-08-12 Issue: Volume: Page:
ISSN:0008-6363
Container-title:Cardiovascular Research
language:en
Short-container-title:

Author:

Reyat Jasmeet S¹²^ORCID,Sommerfeld Laura C¹³⁴⁵^ORCID,O’Reilly Molly¹^ORCID,Roth Cardoso Victor¹⁶^ORCID,Thiemann Ellen³⁴⁷^ORCID,Khan Abdullah O¹^ORCID,O’Shea Christopher¹^ORCID,Harder Sönke⁸^ORCID,Müller Christian⁹,Barlow Jonathan¹⁰^ORCID,Stapley Rachel J¹^ORCID,Chua Winnie¹^ORCID,Kabir S Nashitha¹^ORCID,Grech Olivia¹^ORCID,Hummel Oliver¹¹^ORCID,Hübner Norbert¹¹¹²¹³^ORCID,Kääb Stefan¹⁴¹⁵^ORCID,Mont Lluis¹⁶¹⁷¹⁸^ORCID,Hatem Stéphane N¹⁹,Winters Joris²⁰^ORCID,Zeemering Stef²⁰^ORCID,Morgan Neil V¹^ORCID,Rayes Julie¹^ORCID,Gehmlich Katja¹^ORCID,Stoll Monika²¹²²^ORCID,Brand Theresa²³^ORCID,Schweizer Michaela²⁴^ORCID,Piasecki Angelika⁷,Schotten Ulrich²⁰^ORCID,Gkoutos Georgios V⁶^ORCID,Lorenz Kristina²³²⁵^ORCID,Cuello Friederike⁴⁷^ORCID,Kirchhof Paulus¹³⁴^ORCID,Fabritz Larissa¹³⁴⁵^ORCID

Affiliation:

1. Institute of Cardiovascular Sciences, College of Medical and Dental Sciences, University of Birmingham , Wolfson Drive, B15 2TT Birmingham , UK

2. Division of Cardiovascular Medicine, Radcliffe Department of Medicine, University of Oxford, John Radcliffe Hospital , OX3 9DU Oxford , UK

3. Department of Cardiology, University Heart and Vascular Center Hamburg, University Medical Center Hamburg-Eppendorf , Martinistraße 52, 20246 Hamburg , Germany

4. DZHK (German Center for Cardiovascular Research), Partner Site Hamburg/Kiel/Lübeck, University Medical Center Hamburg-Eppendorf , Martinistraße 52, 20246 Hamburg , Germany

5. University Center of Cardiovascular Sciences, University Medical Center Hamburg-Eppendorf , Martinistraße 52, 20246 Hamburg , Germany

6. Institute of Cancer Genomics, College of Medical and Dental Sciences, University of Birmingham , B15 2TT Birmingham , UK

7. Institute of Experimental Pharmacology and Toxicology, Cardiovascular Research Center, University Medical Center Hamburg-Eppendorf , Martinistrasse 52, 20246 Hamburg , Germany

8. Institut für Klinische Chemie und Laboratoriumsmedizin, Massenspektrometrische Proteomanalytik, University Medical Center Hamburg-Eppendorf , Martinistrasse 52, 20246 Hamburg , Germany

9. UKE Bioinformatics Core, University Medical Center Hamburg-Eppendorf , Martinistrasse 52, 20246 Hamburg , Germany

10. Cellular Health and Metabolism Facility, College of Life and Environmental Sciences, University of Birmingham , B15 2TT Birmingham , UK

11. Max Delbrück Centrum for Molecular Medicine , Robert-Rössle-Straße 10, 13125 Berlin , Germany

12. Charite—Universitätsmedizin Berlin , Charitéplatz 1, 10117 Berlin , Germany

13. DZHK (German Center for Cardiovascular Research), Partner Site Berlin , Germany

14. Department of Medicine I, University Hospital Munich, Ludwig Maximilian University of Munich (LMU) , Marchioninistraße 15, 81377 Munich , Germany

15. DZHK (German Centre for Cardiovascular Research), Partner Site Munich Heart Alliance , Munich , Germany

16. Hospital Clínic, Universitat de Barcelona , Villarroel, 170, 08036, Barcelona, Catalonia , Spain

17. Institut de Recerca Biomèdica, August Pi- i Sunyer , Roselló, 149-153, 08036 Barcelona, Catalonia , Spain

18. Centro Investigación Biomedica en Red Cardiovascular , Av. Monforte de Lemos, 3-5. Pabellón 11. Planta 0, 28029 Madrid , Spain

19. INSERM UMRS1166, ICAN—Institute of Cardiometabolism and Nutrition, Sorbonne University, Institute of Cardiology, Pitié-Salpêtrière Hospital , 91 Boulevard de l’Hôpital, 75013 Paris , France

20. Department of Physiology, Cardiovascular Research Institute Maastricht, Maastricht University , Minderbroedersberg 4-66211 LK Maastricht , The Netherlands

21. Institute of Human Genetics, Genetic Epidemiology , WWU Münster, Albert-Schweitzer-Campus 1, D3, Domagkstraße 3, 48149 Münster , Germany

22. Cardiovascular Research Institute Maastricht, Genetic Epidemiology and Statistical Genetics, Maastricht University , Universiteitssingel 50, 6229 ER Maastricht , The Netherlands

23. Institute of Pharmacology and Toxicology, University of Würzburg , Versbacher Straße 9, 97078 Würzburg , Germany

24. Department of Morphology and Electron Microscopy, Center for Molecular Neurobiology, University Medical Center Hamburg-Eppendorf , Martinistraße 52, 20246 Hamburg , Germany

25. Leibniz-Institut für Analytische Wissenschaften—ISAS—e.V. , ISAS City, Bunsen-Kirchhoff-Straße 11, 44139 Dortmund , Germany

Abstract

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.

Funder

European Commission

British Heart Foundation

German Centre for Cardiovascular Research

German Ministry of Education and Research

Leducq Foundation

Deutsche Forschungsgemeinschaft

British Heart Foundation Accelerator Award

Medical Research Council

National Centre for the Replacement Refinement & Reduction of Animals in Research

Sir Henry Wellcome Fellows

British Heart Foundation Intermediate Fellow