Impaired Atrial Mitochondrial Calcium Handling in Patients With Atrial Fibrillation

Julius Ryan D Pronto^{1

2}, Fleur E Mason^{1

2}, Eva A Rog-Zielinska³, Funsho E Fakuade^{1

4

2

5

6}, Donata Bülow¹, Marcell Tóth⁶, Khaled Machwart^{7

8}, Paulina Brandes¹, Felix Wiedmann^{2

9

10}, Michael Kohlhaas⁸, Alexander Nickel⁸, Matthias Wolf¹¹, Julian Mustroph^{11

12}, Kim-Chi Vu^{4

13

5}, Sören Brandenburg^{4

13

5}, Tri Q Do¹⁴, Peter Joshua Siedler^{1

2}, Katharina Ritzenhoff^{1

2}, Zongqian Xue^{10

15}, Xiaobo Zhou^{10

15}, Stefanie Kestel^{1

2}, Olga Dschun¹⁶, Oksana Kyshynska¹⁷, George Kensah^{17

2}, Robyn T Rebbeck¹⁸, Aschraf El-Essawi^{17

2}, Ahmad Fawad Jebran^{17

2}, Bernhard C Danner^{17

2

14}, Hassina Baraki^{17

2}, Johann Schredelseker^{19

20}, Ivan Bogeski²¹, Bianca J J M Brundel²², Stephan E Lehnart^{4

13

2

5}, Constanze Bening^{7

8

23}, Ingo Kutschka^{17

2}, Felix Bremmer¹⁶, Stefan M Kallenberger^{24

25}, Silvio O Rizzoli^{26

5}, Björn C Knollmann, Stefan Neef¹¹, Katrin Streckfuss-Bömeke^{6

27}, Constanze Schmidt^{4

2

9

10}, Christoph Maack⁸, Niels Voigt^{1

2

5}

Affiliations

¹ Institute of Pharmacology and Toxicology (J.R.D.P., F.E.M., F.E.F., D.B., P.B., P.J.S., K.R., S.K., N.V.), University Medical Center Göttingen, Germany.
² DZHK (German Centre for Cardiovascular Research), partner site Lower Saxony, Göttingen (J.R.D.P., F.E.M., F.E.F., F.W., P.J.S., K.R., S.K., G.K., A.E.-E., A.F.J., B.C.D., H.B., S.E.L., I.K., C.S., N.V.).
³ Institute for Experimental Cardiovascular Medicine (IEKM), University Heart Center and Faculty of Medicine, University of Freiburg, Germany (E.A.R.-Z.).
⁴ Department of Cardiology and Pneumology (F.W., K.-C.V., S.B., S.E.L., C.S.), University Medical Center Göttingen, Germany.
⁵ Cluster of Excellence "Multiscale Bioimaging: From Molecular Machines to Networks of Excitable Cells" (MBExC), Georg-August-University Göttingen, Germany (F.E.F., K.-C.V., S.B., S.E.L., S.O.R., N.V.).
⁶ Institute of Pharmacology and Toxicology, Julius Maximilian University of Würzburg, Germany (M.T., K.S.-B.).
⁷ Department of Thoracic and Cardiovascular Surgery (K.M., C.B.), University Clinic Würzburg, Germany.
⁸ Comprehensive Heart Failure Center Würzburg (K.M., M.K., A.N., C.B., C.M.), University Clinic Würzburg, Germany.
⁹ Department of Cardiology, Angiology and Pneumology, University Hospital Heidelberg, Germany (F.W., C.S.).
¹⁰ DZHK (German Centre for Cardiovascular Research), partner site Heidelberg/Mannheim, Germany (F.W., Z.X., X.Z., C.S.).
¹¹ Department of Internal Medicine II, University Hospital Regensburg, Germany (M.W., J.M., S.N.).
¹² Department of Pharmacology, University of Regensburg, Germany (J.M.).
¹³ Heart Research Center Göttingen (K.-C.V., S.B., S.E.L.), University Medical Center Göttingen, Germany.
¹⁴ Department of Medicine, Vanderbilt University Medical Center, Nashville, TN (T.Q.D., B.C.K.).
¹⁵ Department of Cardiology, Angiology, Hemostaseology and Medical Intensive Care, Medical Faculty Mannheim, Heidelberg University, Mannheim, Germany (Z.X., X.Z.).
¹⁶ Institute of Pathology (O.D., F.B.), University Medical Center Göttingen, Germany.
¹⁷ Department of Thoracic and Cardiovascular Surgery (O.K., G.K., A.E.-E., A.F.J., B.C.D., H.B., I.K.), University Medical Center Göttingen, Germany.
¹⁸ Department of Biochemistry, Molecular Biology and Biophysics, University of Minnesota, Minneapolis (R.T.R.).
¹⁹ Walther Straub Institute of Pharmacology and Toxicology, Faculty of Medicine, LMU Munich, Germany (J.S.).
²⁰ DZHK (German Centre for Cardiovascular Research), Partner Site Munich Heart Alliance, Germany (J.S.).
²¹ Molecular Physiology, Institute of Cardiovascular Physiology (I.B.), University Medical Center Göttingen, Germany.
²² Department of Physiology, Amsterdam UMC, Location Vrije Universiteit, Amsterdam Cardiovascular Sciences, Heart Failure and Arrhythmias, the Netherlands (B.J.J.M.B.).
²³ Now with Rhein-Neckar Praxis, Eberbach, Germany (C.B.).
²⁴ Health Data Science Unit, University Hospital Heidelberg and Center for Quantitative Analysis of Molecular and Cellular Biosystems (BioQuant), University of Heidelberg, Germany (S. Kallenberger).
²⁵ Department of Medical Oncology, National Center for Tumor Diseases, Heidelberg University Hospital, Germany (S.M.K.).
²⁶ Department of Neuro- and Sensory Physiology (S.O.R.), University Medical Center Göttingen, Germany.
²⁷ Medical Clinic I, Cardiology and Angiology, Justus-Liebig-University, Giessen, Germany (K.S.-B.).

PMID: 41090220
DOI: 10.1161/CIRCRESAHA.124.325658

Free article

Impaired Atrial Mitochondrial Calcium Handling in Patients With Atrial Fibrillation

Julius Ryan D Pronto et al. Circ Res. 2025.

Free article

. 2025 Nov 7;137(11):1333-1352.

doi: 10.1161/CIRCRESAHA.124.325658. Epub 2025 Oct 15.

Authors

Affiliations

¹ Institute of Pharmacology and Toxicology (J.R.D.P., F.E.M., F.E.F., D.B., P.B., P.J.S., K.R., S.K., N.V.), University Medical Center Göttingen, Germany.
² DZHK (German Centre for Cardiovascular Research), partner site Lower Saxony, Göttingen (J.R.D.P., F.E.M., F.E.F., F.W., P.J.S., K.R., S.K., G.K., A.E.-E., A.F.J., B.C.D., H.B., S.E.L., I.K., C.S., N.V.).
³ Institute for Experimental Cardiovascular Medicine (IEKM), University Heart Center and Faculty of Medicine, University of Freiburg, Germany (E.A.R.-Z.).
⁴ Department of Cardiology and Pneumology (F.W., K.-C.V., S.B., S.E.L., C.S.), University Medical Center Göttingen, Germany.
⁵ Cluster of Excellence "Multiscale Bioimaging: From Molecular Machines to Networks of Excitable Cells" (MBExC), Georg-August-University Göttingen, Germany (F.E.F., K.-C.V., S.B., S.E.L., S.O.R., N.V.).
⁶ Institute of Pharmacology and Toxicology, Julius Maximilian University of Würzburg, Germany (M.T., K.S.-B.).
⁷ Department of Thoracic and Cardiovascular Surgery (K.M., C.B.), University Clinic Würzburg, Germany.
⁸ Comprehensive Heart Failure Center Würzburg (K.M., M.K., A.N., C.B., C.M.), University Clinic Würzburg, Germany.
⁹ Department of Cardiology, Angiology and Pneumology, University Hospital Heidelberg, Germany (F.W., C.S.).
¹⁰ DZHK (German Centre for Cardiovascular Research), partner site Heidelberg/Mannheim, Germany (F.W., Z.X., X.Z., C.S.).
¹¹ Department of Internal Medicine II, University Hospital Regensburg, Germany (M.W., J.M., S.N.).
¹² Department of Pharmacology, University of Regensburg, Germany (J.M.).
¹³ Heart Research Center Göttingen (K.-C.V., S.B., S.E.L.), University Medical Center Göttingen, Germany.
¹⁴ Department of Medicine, Vanderbilt University Medical Center, Nashville, TN (T.Q.D., B.C.K.).
¹⁵ Department of Cardiology, Angiology, Hemostaseology and Medical Intensive Care, Medical Faculty Mannheim, Heidelberg University, Mannheim, Germany (Z.X., X.Z.).
¹⁶ Institute of Pathology (O.D., F.B.), University Medical Center Göttingen, Germany.
¹⁷ Department of Thoracic and Cardiovascular Surgery (O.K., G.K., A.E.-E., A.F.J., B.C.D., H.B., I.K.), University Medical Center Göttingen, Germany.
¹⁸ Department of Biochemistry, Molecular Biology and Biophysics, University of Minnesota, Minneapolis (R.T.R.).
¹⁹ Walther Straub Institute of Pharmacology and Toxicology, Faculty of Medicine, LMU Munich, Germany (J.S.).
²⁰ DZHK (German Centre for Cardiovascular Research), Partner Site Munich Heart Alliance, Germany (J.S.).
²¹ Molecular Physiology, Institute of Cardiovascular Physiology (I.B.), University Medical Center Göttingen, Germany.
²² Department of Physiology, Amsterdam UMC, Location Vrije Universiteit, Amsterdam Cardiovascular Sciences, Heart Failure and Arrhythmias, the Netherlands (B.J.J.M.B.).
²³ Now with Rhein-Neckar Praxis, Eberbach, Germany (C.B.).
²⁴ Health Data Science Unit, University Hospital Heidelberg and Center for Quantitative Analysis of Molecular and Cellular Biosystems (BioQuant), University of Heidelberg, Germany (S. Kallenberger).
²⁵ Department of Medical Oncology, National Center for Tumor Diseases, Heidelberg University Hospital, Germany (S.M.K.).
²⁶ Department of Neuro- and Sensory Physiology (S.O.R.), University Medical Center Göttingen, Germany.
²⁷ Medical Clinic I, Cardiology and Angiology, Justus-Liebig-University, Giessen, Germany (K.S.-B.).

PMID: 41090220
DOI: 10.1161/CIRCRESAHA.124.325658

Abstract

Background: Mitochondrial calcium (Ca²⁺) 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 Ca²⁺ transient amplitude, but its effect on mitochondrial Ca²⁺ 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 [Ca²⁺] 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 Ca²⁺ uptake enhancer ezetimibe on proarrhythmic activity in atrial myocytes and on AF burden in patients were investigated.

Results: Mitochondrial Ca²⁺ 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 Ca²⁺ sparks, which were rescued by MitoTEMPO. Ezetimibe also reduced the occurrence of arrhythmogenic Ca²⁺ 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 Ca²⁺ 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 Ca²⁺ transfer in AF. Enhancing mitochondrial Ca²⁺ uptake potentially protects against arrhythmogenic events.

Keywords: atrial fibrillation; calcium signaling; ezetimibe; microtubules; mitochondria.

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Impaired Atrial Mitochondrial Calcium Handling in Patients With Atrial Fibrillation

Affiliations

Impaired Atrial Mitochondrial Calcium Handling in Patients With Atrial Fibrillation

Authors

Affiliations

Abstract

Conflict of interest statement

MeSH terms

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LinkOut - more resources

Full Text Sources

Medical

Miscellaneous