PITX2 deficiency leads to atrial mitochondrial dysfunction

Jasmeet S Reyat; Laura C Sommerfeld; Molly O'Reilly; Victor R 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

doi:10.1093/cvr/cvae169

PITX2 deficiency leads to atrial mitochondrial dysfunction

Jasmeet S Reyat^*, Laura C Sommerfeld, Molly O'Reilly, Victor R 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 WintersStef 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

^*Corresponding author for this work

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

Abstract

AIM: Reduced left atrial PITX2 is associated with atrial cardiomyopathy and atrial fibrillation. PITX2 is restricted to left atrial cardiomyocytes in the adult heart. The links between PITX2 deficiency, atrial cardiomyopathy and atrial fibrillation are not fully understood. METHODS AND RESULTS: To identify mechanisms linking PITX2 deficiency to atrial fibrillation, we generated and characterized PITX2-deficient human atrial cardiomyocytes derived from human induced pluripotent stem cells (hiPSC) and their controls. PITX2-deficient hiPSC-derived atrial cardiomyocytes showed shorter and disorganised sarcomeres and increased mononucleation. Electron microscopy found an increased number of smaller mitochondria compared to the control. 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 atrial fibrillation compared to 43 patients in sinus rhythm. Dysregulation of left atrial mitochondrial (COX7C) and metabolic (FOXO1) genes was associated with PITX2 expression in human left atria. CONCLUSIONS: In summary, PITX2 deficiency causes mitochondrial dysfunction and a metabolic shift to glycolysis in human atrial cardiomyocytes. PITX2-dependent metabolic changes can contribute to the structural and functional defects found in PITX2-deficient atria.

Original language	English
Journal	Cardiovascular Research
DOIs	https://doi.org/10.1093/cvr/cvae169
Publication status	E-pub ahead of print - 12 Aug 2024

Keywords

PITX2
atrial fibrillation
human heart tissue
human induced pluripotent stem cells
metabolic shift
mitochondrial dysfunction

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10.1093/cvr/cvae169

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Reyat, J. S., Sommerfeld, L. C., O'Reilly, M., Cardoso, V. R., Thiemann, E., Khan, A. O., O'Shea, C., Harder, S., 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. Advance online publication. https://doi.org/10.1093/cvr/cvae169

@article{7572a9723be9486da5db29694ad90d94,

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

abstract = "AIM: Reduced left atrial PITX2 is associated with atrial cardiomyopathy and atrial fibrillation. PITX2 is restricted to left atrial cardiomyocytes in the adult heart. The links between PITX2 deficiency, atrial cardiomyopathy and atrial fibrillation are not fully understood. METHODS AND RESULTS: To identify mechanisms linking PITX2 deficiency to atrial fibrillation, we generated and characterized PITX2-deficient human atrial cardiomyocytes derived from human induced pluripotent stem cells (hiPSC) and their controls. PITX2-deficient hiPSC-derived atrial cardiomyocytes showed shorter and disorganised sarcomeres and increased mononucleation. Electron microscopy found an increased number of smaller mitochondria compared to the control. 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 atrial fibrillation compared to 43 patients in sinus rhythm. Dysregulation of left atrial mitochondrial (COX7C) and metabolic (FOXO1) genes was associated with PITX2 expression in human left atria. CONCLUSIONS: In summary, PITX2 deficiency causes mitochondrial dysfunction and a metabolic shift to glycolysis in human atrial cardiomyocytes. PITX2-dependent metabolic changes can contribute to the structural and functional defects found in PITX2-deficient atria.",

keywords = "PITX2, atrial fibrillation, human heart tissue, human induced pluripotent stem cells, metabolic shift, mitochondrial dysfunction",

author = "Reyat, {Jasmeet S} and Sommerfeld, {Laura C} and Molly O'Reilly and Cardoso, {Victor R} and Ellen Thiemann and Khan, {Abdullah O} and Christopher O'Shea and S{\"o}nke Harder 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 = aug,

day = "12",

doi = "10.1093/cvr/cvae169",

language = "English",

journal = "Cardiovascular Research",

issn = "0008-6363",

publisher = "Oxford University Press",

}

Reyat, JS, Sommerfeld, LC, O'Reilly, M, Cardoso, VR, Thiemann, E, Khan, AO, O'Shea, C, Harder, S, 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. 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 - Cardoso, Victor R

AU - Thiemann, Ellen

AU - Khan, Abdullah O

AU - O'Shea, Christopher

AU - Harder, Sönke

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 - 2024/8/12

Y1 - 2024/8/12

N2 - AIM: Reduced left atrial PITX2 is associated with atrial cardiomyopathy and atrial fibrillation. PITX2 is restricted to left atrial cardiomyocytes in the adult heart. The links between PITX2 deficiency, atrial cardiomyopathy and atrial fibrillation are not fully understood. METHODS AND RESULTS: To identify mechanisms linking PITX2 deficiency to atrial fibrillation, we generated and characterized PITX2-deficient human atrial cardiomyocytes derived from human induced pluripotent stem cells (hiPSC) and their controls. PITX2-deficient hiPSC-derived atrial cardiomyocytes showed shorter and disorganised sarcomeres and increased mononucleation. Electron microscopy found an increased number of smaller mitochondria compared to the control. 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 atrial fibrillation compared to 43 patients in sinus rhythm. Dysregulation of left atrial mitochondrial (COX7C) and metabolic (FOXO1) genes was associated with PITX2 expression in human left atria. CONCLUSIONS: In summary, PITX2 deficiency causes mitochondrial dysfunction and a metabolic shift to glycolysis in human atrial cardiomyocytes. PITX2-dependent metabolic changes can contribute to the structural and functional defects found in PITX2-deficient atria.

AB - AIM: Reduced left atrial PITX2 is associated with atrial cardiomyopathy and atrial fibrillation. PITX2 is restricted to left atrial cardiomyocytes in the adult heart. The links between PITX2 deficiency, atrial cardiomyopathy and atrial fibrillation are not fully understood. METHODS AND RESULTS: To identify mechanisms linking PITX2 deficiency to atrial fibrillation, we generated and characterized PITX2-deficient human atrial cardiomyocytes derived from human induced pluripotent stem cells (hiPSC) and their controls. PITX2-deficient hiPSC-derived atrial cardiomyocytes showed shorter and disorganised sarcomeres and increased mononucleation. Electron microscopy found an increased number of smaller mitochondria compared to the control. 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 atrial fibrillation compared to 43 patients in sinus rhythm. Dysregulation of left atrial mitochondrial (COX7C) and metabolic (FOXO1) genes was associated with PITX2 expression in human left atria. CONCLUSIONS: In summary, PITX2 deficiency causes mitochondrial dysfunction and a metabolic shift to glycolysis in human atrial cardiomyocytes. PITX2-dependent metabolic changes can contribute to the structural and functional defects found in PITX2-deficient atria.

KW - PITX2

KW - atrial fibrillation

KW - human heart tissue

KW - human induced pluripotent stem cells

KW - metabolic shift

KW - mitochondrial dysfunction

U2 - 10.1093/cvr/cvae169

DO - 10.1093/cvr/cvae169

M3 - Article

SN - 0008-6363

JO - Cardiovascular Research

JF - Cardiovascular Research

ER -

PITX2 deficiency leads to atrial mitochondrial dysfunction

Abstract

Keywords

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