PITX2 deficiency leads to atrial mitochondrial dysfunction

Jasmeet S. Reyat; Laura C. Sommerfeld; Molly O'Reilly; Victor Roth Cardoso; Ellen Thiemann; Abdullah O. Khan; Christopher O'Shea; S. nke 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

doi:10.1093/cvr/cvae169

PITX2 deficiency leads to atrial mitochondrial dysfunction

Jasmeet S. Reyat
, Laura C. Sommerfeld
, Molly O'Reilly
, Victor Roth Cardoso
, Ellen Thiemann
, Abdullah O. Khan
, Christopher O'Shea
, S. nke 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

University of Birmingham
University of Oxford
University of Hamburg
Institute of Cardiovascular Sciences, College of Medical and Dental Sciences, University of Birmingham, Wolfson Drive, B15 2TT Birmingham, UK
Max Delbrück Center for Molecular Medicine in the Helmholtz Association
Charité – Universitätsmedizin Berlin
German Centre for Cardiovascular Research
Ludwig Maximilian University of Munich
University of Barcelona
Institute for Research in Biomedicine
Av. Monforte de Lemos
Sorbonne Université
Maastricht University
University of Münster
University of Würzburg
Leibniz-Institut für Analytische Wissenschaften

Research output: Contribution to journal › Article › Academic › peer-review

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.

Original language	English
Pages (from-to)	1907-1923
Journal	Cardiovascular research
Volume	120
Issue number	15
DOIs	https://doi.org/10.1093/cvr/cvae169
Publication status	Published - 4 Dec 2024
Externally published	Yes

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

SDG 3 Good Health and Well-being

Access to Document

10.1093/cvr/cvae169

Cite this

Reyat, J. S., Sommerfeld, L. C., O'Reilly, M., Roth Cardoso, V., Thiemann, E., Khan, A. O., O'Shea, C., Harder, S. N., Müller, C., Barlow, J., Stapley, R. J., Chua, W., Kabir, S. N., Grech, O., Hummel, O., Hübner, N., Kääb, S., Mont, L., Hatem, S. N., ... Fabritz, L. (2024). PITX2 deficiency leads to atrial mitochondrial dysfunction. Cardiovascular research, 120(15), 1907-1923. https://doi.org/10.1093/cvr/cvae169

@article{944cbf7efe554891b19d3f43f86b791f,

title = "PITX2 deficiency leads to atrial mitochondrial dysfunction",

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.",

author = "Reyat, \{Jasmeet S.\} and Sommerfeld, \{Laura C.\} and Molly O'Reilly and \{Roth Cardoso\}, Victor and Ellen Thiemann and Khan, \{Abdullah O.\} and Christopher O'Shea and Harder, \{S. nke\} and Christian M{\"u}ller and Jonathan Barlow and Stapley, \{Rachel J.\} and Winnie Chua and Kabir, \{S. Nashitha\} and Olivia Grech and Oliver Hummel and Norbert H{\"u}bner and Stefan K{\"a}{\"a}b and Lluis Mont and Hatem, \{St{\'e}phane N.\} and Joris Winters and Stef Zeemering and Morgan, \{Neil V.\} and Julie Rayes and Katja Gehmlich and Monika Stoll and Theresa Brand and Michaela Schweizer and Angelika Piasecki and Ulrich Schotten and Gkoutos, \{Georgios V.\} and Kristina Lorenz and Friederike Cuello and Paulus Kirchhof and Larissa Fabritz",

year = "2024",

month = dec,

day = "4",

doi = "10.1093/cvr/cvae169",

language = "English",

volume = "120",

pages = "1907--1923",

journal = "Cardiovascular research",

issn = "0008-6363",

publisher = "Oxford University Press",

number = "15",

}

Reyat, JS, Sommerfeld, LC, O'Reilly, M, Roth Cardoso, V, Thiemann, E, Khan, AO, O'Shea, C, Harder, SN, Müller, C, Barlow, J, Stapley, RJ, Chua, W, Kabir, SN, Grech, O, Hummel, O, Hübner, N, Kääb, S, Mont, L, Hatem, SN, Winters, J, Zeemering, S, Morgan, NV, Rayes, J, Gehmlich, K, Stoll, M, Brand, T, Schweizer, M, Piasecki, A, Schotten, U, Gkoutos, GV, Lorenz, K, Cuello, F, Kirchhof, P & Fabritz, L 2024, 'PITX2 deficiency leads to atrial mitochondrial dysfunction', Cardiovascular research, vol. 120, no. 15, pp. 1907-1923. https://doi.org/10.1093/cvr/cvae169

TY - JOUR

T1 - PITX2 deficiency leads to atrial mitochondrial dysfunction

AU - Reyat, Jasmeet S.

AU - Sommerfeld, Laura C.

AU - O'Reilly, Molly

AU - Roth Cardoso, Victor

AU - Thiemann, Ellen

AU - Khan, Abdullah O.

AU - O'Shea, Christopher

AU - Harder, S. nke

AU - Müller, Christian

AU - Barlow, Jonathan

AU - Stapley, Rachel J.

AU - Chua, Winnie

AU - Kabir, S. Nashitha

AU - Grech, Olivia

AU - Hummel, Oliver

AU - Hübner, Norbert

AU - Kääb, Stefan

AU - Mont, Lluis

AU - Hatem, Stéphane N.

AU - Winters, Joris

AU - Zeemering, Stef

AU - Morgan, Neil V.

AU - Rayes, Julie

AU - Gehmlich, Katja

AU - Stoll, Monika

AU - Brand, Theresa

AU - Schweizer, Michaela

AU - Piasecki, Angelika

AU - Schotten, Ulrich

AU - Gkoutos, Georgios V.

AU - Lorenz, Kristina

AU - Cuello, Friederike

AU - Kirchhof, Paulus

AU - Fabritz, Larissa

PY - 2024/12/4

Y1 - 2024/12/4

N2 - 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.

AB - 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.

UR - https://www.scopus.com/pages/publications/85210068070

UR - https://www.ncbi.nlm.nih.gov/pubmed/39129206

U2 - 10.1093/cvr/cvae169

DO - 10.1093/cvr/cvae169

M3 - Article

C2 - 39129206

SN - 0008-6363

VL - 120

SP - 1907

EP - 1923

JO - Cardiovascular research

JF - Cardiovascular research

IS - 15

ER -

PITX2 deficiency leads to atrial mitochondrial dysfunction

Abstract

UN SDGs

Access to Document

Other files and links

Fingerprint

Cite this