Impaired Atrial Mitochondrial Calcium Handling in Patients With Atrial Fibrillation
Year: 2025
Type: article
Abstract: BACKGROUND: Mitochondrial calcium (Ca 2+ ) is a key regulator of cardiac energetics by stimulating the tricarboxylic acid cycle during elevated workload. Atrial fibrillation (AF) is associated with a reduction in cytosolic Ca 2+ transient amplitude, but its effect on mitochondrial Ca 2+ handling and cellular redox state has not been explored. METHODS: Cardiac myocytes isolated from patient-derived right atrial biopsies were subjected to workload transitions using patch-clamp stimulation and β-adrenergic stimulation (isoproterenol). In conjunction, nicotinamide adenine dinucleotide (phosphate)/flavin adenine dinucleotide (NAD[P]H/FAD) autofluorescence, cytosolic and mitochondrial [Ca 2+ ] were monitored using epifluorescence microscopy. Sarcoplasmic reticulum and mitochondria were imaged using electron microscopy and tomography and stimulated emission depletion microscopy. The effects of the mitochondrial Ca 2+ uptake enhancer ezetimibe on proarrhythmic activity in atrial myocytes and on AF burden in patients were investigated. RESULTS: Mitochondrial Ca 2+ accumulation during increased workload was blunted in AF, and was associated with impaired regeneration of nicotinamide adenine dinucleotide and flavin adenine dinucleotide. Nanoscale imaging revealed spatial disorganization of sarcoplasmic reticulum and mitochondria, associated with microtubule destabilization. This was confirmed in human induced pluripotent stem cell–derived cardiac myocytes, where treatment with the microtubule destabilizer nocodazole displaced mitochondria and increased proarrhythmic Ca 2+ sparks, which were rescued by MitoTEMPO. Ezetimibe also reduced the occurrence of arrhythmogenic Ca 2+ release events both in AF myocytes and nocodazole-treated human induced pluripotent stem cell–derived cardiac myocytes. Retrospective patient analysis also revealed a reduced AF burden in patients on ezetimibe treatment. CONCLUSIONS: Mitochondrial Ca 2+ uptake and accumulation are impaired in atrial myocytes from patients with AF. The disturbed spatial association between sarcoplasmic reticulum and mitochondria driven by destabilized microtubules may underlie impaired Ca 2+ transfer in AF. Enhancing mitochondrial Ca 2+ uptake potentially protects against arrhythmogenic events.
Source: Circulation Research
Authors: Julius Ryan D. Pronto, Fleur E. Mason, Eva A. Rog-Zielinska, Funsho E. Fakuade, Donata Bülow, Marcell Tóth, Khaled Machwart, Paulina Brandes, Felix Wiedmann, Michael Kohlhaas, Alexander Nickel, Matthias Wolf, Julian Mustroph, Kim-Chi Vu, Sören Brandenburg, Tri Q. Do, Peter Joshua Siedler, Katharina Ritzenhoff, Zongqian Xue, Xiaobo Zhou, Stefanie Kestel, Olga Dschun, Oksana Kyshynska, George Kensah, Robyn T. Rebbeck, Aschraf El-Essawi, Ahmad Fawad Jebran, Bernhard C. Danner, Hassina Baraki, Johann Schredelseker, Ivan Bogeski, Bianca J.J.M. Brundel, Stephan E. Lehnart, Constanze Bening, Ingo Kutschka, Felix Bremmer, Stefan M. Kallenberger, Silvio O. Rizzoli, Björn C. Knollmann, Stefan Neef, Katrin Streckfuss-Bömeke, Constanze Schmidt, Christoph Maack, Niels Voigt
Institutions: Universitätsmedizin Göttingen, German Centre for Cardiovascular Research, University of Göttingen, University of Freiburg, Universitäts-Herzzentrum Freiburg-Bad Krozingen, University of Würzburg, Multiscale Bioimaging, Universitätsklinikum Würzburg, Heidelberg University, University Hospital Heidelberg, University Hospital Regensburg, University of Regensburg, Vanderbilt University Medical Center, Medizinische Fakultät Mannheim, University of Minnesota, Walther-Straub-Institut für Pharmakologie und Toxikologie, Ludwig-Maximilians-Universität München, Amsterdam Cardiovascular Sciences, Amsterdam UMC Location Vrije Universiteit Amsterdam, National Center for Tumor Diseases, Justus-Liebig-Universität Gießen
Language: English
Subfield: Cardiology and Cardiovascular Medicine
Field: Medicine
Domain: Health Sciences
Open Access status: hybrid
Funders: Florida Education Fund, Vanderbilt University, University of Minnesota, Deutsches Zentrum für Herz-Kreislaufforschung, Vanderbilt University Medical Center, Universitätsmedizin Göttingen, Amsterdam University Medical Centers, Deutsche Forschungsgemeinschaft, Universität Heidelberg, Albert-Ludwigs-Universität Freiburg, Else Kröner-Fresenius-Stiftung, Nederlandse Organisatie voor Wetenschappelijk Onderzoek, Universitätsklinikum Regensburg, Universität Regensburg, Ludwig-Maximilians-Universität München, Deutsche Herzstiftung, Julius-Maximilians-Universität Würzburg, Universitätsklinikum Heidelberg, National Institutes of Health, Amsterdam Cardiovascular Sciences, Amsterdam University Medical Centers, Medizinische Fakultät der Albert-Ludwigs-Universität Freiburg, National Center for Advancing Translational Sciences, Common Fund
Award: G756744335
OpenAlex ID: W4415208774