Bioenergetic and metabolic aberrations in induced pluripotent stem cell-derived cardiomyocytes generated from a patient with Wolff-Parkinson-White syndrome caused a PRKAG2 mutation

Polina Baskin; Ifat Abramovich; Helena Milman; Ronen Ben Jehuda; Bella Agranovich; Mor Davidor; Valerie Buffard; Todd Herron; Ferhaan Ahmad; Michael Arad; Melanie Ricke-Hoch; Ofer Binah

doi:10.3389/fcvm.2026.1719965

Back

Bioenergetic and metabolic aberrations in induced pluripotent stem cell-derived cardiomyocytes generated from a patient with Wolff-Parkinson-White syndrome caused a PRKAG2 mutation

Journal article

Open access

Peer reviewed

Bioenergetic and metabolic aberrations in induced pluripotent stem cell-derived cardiomyocytes generated from a patient with Wolff-Parkinson-White syndrome caused a PRKAG2 mutation

Polina Baskin, Ifat Abramovich, Helena Milman, Ronen Ben Jehuda, Bella Agranovich, Mor Davidor, Valerie Buffard, Todd Herron, Ferhaan Ahmad, Michael Arad, …

Frontiers in cardiovascular medicine, Vol.13, 1719965

04/10/2026

DOI: 10.3389/fcvm.2026.1719965

Files and links (1)

url

https://doi.org/10.3389/fcvm.2026.1719965View

Published (Version of record) Open Access

Abstract

Introduction: The PRKAG2 gene encodes the AMPK (AMP-activated protein kinase) γ2 subunit, regulating cellular energy homeostasis. PRKAG2 mutations such as R302Q are associated with familial Wolff-Parkinson-White syndrome and hypertrophic cardiomyopathy, leading to metabolic dysregulation and cardiac dysfunction. Accordingly, we hypothesized that PRKAG2R302Q mutation is associated with cardiac bioenergetic/metabolic deficits, causing cardiac dysfunction. Methods: Using WPW patient' iPSC-derived cardiomyocytes (iPSC-CMs) and a murine model carrying a PRKAG2 mutation, we investigated the mutations-associated functional abnormalities. Results: We found in mutant iPSC-CMs compared to health iPSC-CMs, reduced glycolytic function and increased maximal mitochondrial respiration associated with elevated mitochondrial content, alongside increased glycogen accumulation, lipid storage and alterations in pathways related to redox regulation. Mutated murine hearts exhibited glycogen accumulation, altered glucose and lipid metabolism, elevated triacylglycerol levels and enhanced fatty acid oxidation pathways. Lipidomic and metabolomic analyses in both models revealed disrupted pathways linked to glucose and lipid metabolism. RNA-seq identified gene expression changes associated with redox regulation, mitochondrial function and hypertrophic signaling, aligned with the observed cellular and tissue-level dysfunction. Metformin treatment reduced mitochondrial content and respiration in mutant iPSC-CMs and significantly attenuated the arrhythmias. Discussion: These findings increase our understanding of PRKAG2-associated cardiomyopathy, and propose metformin as a novel modality for managing the metabolic and electrophysiological aberrations of this genetic disorder.

bioenergetic and metabolic profiling

calcium transients

iPSC-derived cardiomyocytes(iPSC-CMs) from a Wolf-Parkinson-White (WPW) patient

the <italic>PRKAG2</italic> gene

transgenic mice carrying the <italic>PRKAG2</italic> thr400Asn (T400N) mutation (TGT400N)

Wolf-Parkinson-White syndrome (WPW)

Details

Title: Subtitle: Bioenergetic and metabolic aberrations in induced pluripotent stem cell-derived cardiomyocytes generated from a patient with Wolff-Parkinson-White syndrome caused a PRKAG2 mutation
Creators: Polina Baskin - Rappaport Family Institute for Research in the Medical Sciences
Ifat Abramovich - Rappaport Family Institute for Research in the Medical Sciences
Helena Milman - Rappaport Family Institute for Research in the Medical Sciences
Ronen Ben Jehuda - Rappaport Family Institute for Research in the Medical Sciences
Bella Agranovich - Rappaport Family Institute for Research in the Medical Sciences
Mor Davidor - Rappaport Family Institute for Research in the Medical Sciences
Valerie Buffard - University of Iowa
Todd Herron - University of Michigan
Ferhaan Ahmad - University of Iowa
Michael Arad - Sheba Medical Center
Melanie Ricke-Hoch - Medizinische Hochschule Hannover
Ofer Binah - Rappaport Family Institute for Research in the Medical Sciences
Resource Type: Journal article
Publication Details: Frontiers in cardiovascular medicine, Vol.13, 1719965
DOI: 10.3389/fcvm.2026.1719965
ISSN: 2297-055X
eISSN: 2297-055X
Publisher: FRONTIERS MEDIA SA
Grant note: Lower Saxony Ministry of Science and Culture (Niedersaechsisches Vorab): VW-ZN3452 US-Israel Binational Foundation (BSF): 2019039 Rappaport Research Institute: 01012020RI Israel Science Foundation (ISF): 824/19, 15/10/25
The author(s) declared that financial support was received for this work and/or its publication. This work was supported by the Lower Saxony Ministry of Science and Culture (Niedersaechsisches Vorab, VW-ZN3452 to OB and MR-H), the US-Israel Binational Foundation (BSF) (#2019039 to OB and MA), the Rappaport Research Institute (#01012020RI to OB), and the Israel Science Foundation (ISF) (#824/19 and #15/10/25 to OB and MA).
Language: English
Date published: 04/10/2026
Academic Unit: Radiology; Molecular Physiology and Biophysics; Cardiovascular Medicine; Fraternal Order of Eagles Diabetes Research Center; Internal Medicine
Record Identifier: 9985153531302771

Metrics

1 Record Views