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Article

Mitochondrial Dysfunction Underlies Cardiomyocyte Remodeling in Experimental and Clinical Atrial Fibrillation

1
Department of Physiology, Amsterdam UMC, Vrije Universiteit Amsterdam, Amsterdam Cardiovascular Sciences, 1081 HV Amsterdam, The Netherlands
2
Laboratory for Myology, Department of Human Movement Sciences, Faculty of Behavioral and Movement Sciences, Vrije Universiteit Amsterdam, Amsterdam Movement Sciences, 1105 AZ Amsterdam, The Netherlands
3
Laboratory Genetic Metabolic Diseases, Amsterdam UMC, University of Amsterdam, Amsterdam Gastroenterology and Metabolism, Amsterdam Cardiovascular Sciences, 1105 AZ Amsterdam, The Netherlands
4
Department of Cardiology, Erasmus Medical Center, 3015 DG Rotterdam, The Netherlands
5
Department of Clinical Pharmacy and Pharmacology, University Medical Center Groningen, 9700 RB Groningen, The Netherlands
*
Authors to whom correspondence should be addressed.
Cells 2019, 8(10), 1202; https://doi.org/10.3390/cells8101202
Received: 19 August 2019 / Revised: 1 October 2019 / Accepted: 3 October 2019 / Published: 5 October 2019
(This article belongs to the Special Issue The Role of Proteostasis Derailment in Cardiac Diseases)
Atrial fibrillation (AF), the most common progressive tachyarrhythmia, results in structural remodeling which impairs electrical activation of the atria, rendering them increasingly permissive to the arrhythmia. Previously, we reported on endoplasmic reticulum stress and NAD+ depletion in AF, suggesting a role for mitochondrial dysfunction in AF progression. Here, we examined mitochondrial function in experimental model systems for AF (tachypaced HL-1 atrial cardiomyocytes and Drosophila melanogaster) and validated findings in clinical AF. Tachypacing of HL-1 cardiomyocytes progressively induces mitochondrial dysfunction, evidenced by impairment of mitochondrial Ca2+-handling, upregulation of mitochondrial stress chaperones and a decrease in the mitochondrial membrane potential, respiration and ATP production. Atrial biopsies from AF patients display mitochondrial dysfunction, evidenced by aberrant ATP levels, upregulation of a mitochondrial stress chaperone and fragmentation of the mitochondrial network. The pathophysiological role of mitochondrial dysfunction is substantiated by the attenuation of AF remodeling by preventing an increased mitochondrial Ca2+-influx through partial blocking or downregulation of the mitochondrial calcium uniporter, and by SS31, a compound that improves bioenergetics in mitochondria. Together, these results show that conservation of the mitochondrial function protects against tachypacing-induced cardiomyocyte remodeling and identify this organelle as a potential novel therapeutic target. View Full-Text
Keywords: atrial fibrillation; mitochondria; MCU; Ru360; SS31 atrial fibrillation; mitochondria; MCU; Ru360; SS31
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MDPI and ACS Style

Wiersma, M.; van Marion, D.M.S.; Wüst, R.C.I.; Houtkooper, R.H.; Zhang, D.; de Groot, N.M.S.; Henning, R.H.; Brundel, B.J.J.M. Mitochondrial Dysfunction Underlies Cardiomyocyte Remodeling in Experimental and Clinical Atrial Fibrillation. Cells 2019, 8, 1202. https://doi.org/10.3390/cells8101202

AMA Style

Wiersma M, van Marion DMS, Wüst RCI, Houtkooper RH, Zhang D, de Groot NMS, Henning RH, Brundel BJJM. Mitochondrial Dysfunction Underlies Cardiomyocyte Remodeling in Experimental and Clinical Atrial Fibrillation. Cells. 2019; 8(10):1202. https://doi.org/10.3390/cells8101202

Chicago/Turabian Style

Wiersma, Marit, Denise M.S. van Marion, Rob C.I. Wüst, Riekelt H. Houtkooper, Deli Zhang, Natasja M.S. de Groot, Robert H. Henning, and Bianca J.J.M. Brundel 2019. "Mitochondrial Dysfunction Underlies Cardiomyocyte Remodeling in Experimental and Clinical Atrial Fibrillation" Cells 8, no. 10: 1202. https://doi.org/10.3390/cells8101202

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