Conditional ablation of MCU exacerbated cardiac pathology in a genetic arrhythmic model of CPVT
Background: Catecholaminergic polymorphic ventricular tachycardia (CPVT) is a genetic arrhythmic syndrome caused by mutations in the calcium (Ca2+) release channel ryanodine receptor (RyR2) and its accessory proteins. These mutations make the channel leaky, resulting in Ca2+-dependent arrhythmias. B...
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Elsevier
2024-12-01
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| Series: | Journal of Molecular and Cellular Cardiology Plus |
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| Online Access: | http://www.sciencedirect.com/science/article/pii/S2772976124000333 |
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| author | Arpita Deb Brian D. Tow Jie Hao Branden L. Nguyen Valeria Gomez James A. Stewart, Jr Ashley J. Smuder Bjorn C. Knollmann Ying Wang Bin Liu |
| author_facet | Arpita Deb Brian D. Tow Jie Hao Branden L. Nguyen Valeria Gomez James A. Stewart, Jr Ashley J. Smuder Bjorn C. Knollmann Ying Wang Bin Liu |
| author_sort | Arpita Deb |
| collection | DOAJ |
| description | Background: Catecholaminergic polymorphic ventricular tachycardia (CPVT) is a genetic arrhythmic syndrome caused by mutations in the calcium (Ca2+) release channel ryanodine receptor (RyR2) and its accessory proteins. These mutations make the channel leaky, resulting in Ca2+-dependent arrhythmias. Besides arrhythmias, CPVT hearts typically lack structural cardiac remodeling, a characteristic often observed in other cardiac conditions (heart failure, prediabetes) also marked by RyR2 leak. Recent studies suggest that mitochondria are able to accommodate more Ca2+ influx to inhibit arrhythmias in CPVT. Thus, we hypothesize that CPVT mitochondria can absorb diastolic Ca2+ to protect the heart from cardiac remodeling. Methods and results: The Mitochondrial Ca2+ uniporter (MCU), the main mitochondrial Ca2+ uptake protein, was conditionally knocked out in a CPVT model of calsequestrin 2 (CASQ2) KO. In vivo cardiac function was impaired in the CASQ2−/−-MCUCKO model as assessed by echocardiography. Cardiac dilation and cellular hypertrophy were also observed in the CASQ2−/−-MCUCKO hearts. Live-cell imaging identified altered Ca2+ handling and increased oxidative stress in CASQ2−/−-MCUCKO myocytes. The activation status of Ca2+-dependent remodeling pathways (CaMKII, Calcineurin) was not altered in the CASQ2−/−-MCUCKO model. RNAseq identified changes in the transcriptome of the CASQ2−/−-MCUCKO hearts, distinct from the classic cardiac remodeling program of fetal gene re-expression. Conclusions: We present genetic evidence that mitochondria play a protective role in CPVT. MCU-dependent Ca2+ uptake is crucial for preventing pathological cardiac remodeling in CPVT. |
| format | Article |
| id | doaj-art-0d1bf4464fc44ee5952fe594a9b9b7b8 |
| institution | Kabale University |
| issn | 2772-9761 |
| language | English |
| publishDate | 2024-12-01 |
| publisher | Elsevier |
| record_format | Article |
| series | Journal of Molecular and Cellular Cardiology Plus |
| spelling | doaj-art-0d1bf4464fc44ee5952fe594a9b9b7b82024-12-15T06:19:08ZengElsevierJournal of Molecular and Cellular Cardiology Plus2772-97612024-12-0110100093Conditional ablation of MCU exacerbated cardiac pathology in a genetic arrhythmic model of CPVTArpita Deb0Brian D. Tow1Jie Hao2Branden L. Nguyen3Valeria Gomez4James A. Stewart, Jr5Ashley J. Smuder6Bjorn C. Knollmann7Ying Wang8Bin Liu9Department of Biological Sciences, Mississippi State University, Starkville, MS 39762, USADepartment of Biological Sciences, Mississippi State University, Starkville, MS 39762, USAPlant Pathology Department, University of Florida, Gainesville, FL 32611, USADepartment of Applied Physiology and Kinesiology, University of Florida, Gainesville, FL 32611, USAFood Science and Human Nutrition Department, University of Florida, Gainesville, FL 32611, USASchool of Pharmacy, Department of BioMolecular Sciences, University of Mississippi, Oxford, MS 38677, USADepartment of Applied Physiology and Kinesiology, University of Florida, Gainesville, FL 32611, USADepartment of Medicine, Vanderbilt University School of Medicine, Nashville, TN 37232, USADepartment of Biological Sciences, Mississippi State University, Starkville, MS 39762, USA; Plant Pathology Department, University of Florida, Gainesville, FL 32611, USADepartment of Biological Sciences, Mississippi State University, Starkville, MS 39762, USA; Food Science and Human Nutrition Department, University of Florida, Gainesville, FL 32611, USA; Corresponding author at: room 359, 572 Newell Dr, Gainesville, FL 32611, USA.Background: Catecholaminergic polymorphic ventricular tachycardia (CPVT) is a genetic arrhythmic syndrome caused by mutations in the calcium (Ca2+) release channel ryanodine receptor (RyR2) and its accessory proteins. These mutations make the channel leaky, resulting in Ca2+-dependent arrhythmias. Besides arrhythmias, CPVT hearts typically lack structural cardiac remodeling, a characteristic often observed in other cardiac conditions (heart failure, prediabetes) also marked by RyR2 leak. Recent studies suggest that mitochondria are able to accommodate more Ca2+ influx to inhibit arrhythmias in CPVT. Thus, we hypothesize that CPVT mitochondria can absorb diastolic Ca2+ to protect the heart from cardiac remodeling. Methods and results: The Mitochondrial Ca2+ uniporter (MCU), the main mitochondrial Ca2+ uptake protein, was conditionally knocked out in a CPVT model of calsequestrin 2 (CASQ2) KO. In vivo cardiac function was impaired in the CASQ2−/−-MCUCKO model as assessed by echocardiography. Cardiac dilation and cellular hypertrophy were also observed in the CASQ2−/−-MCUCKO hearts. Live-cell imaging identified altered Ca2+ handling and increased oxidative stress in CASQ2−/−-MCUCKO myocytes. The activation status of Ca2+-dependent remodeling pathways (CaMKII, Calcineurin) was not altered in the CASQ2−/−-MCUCKO model. RNAseq identified changes in the transcriptome of the CASQ2−/−-MCUCKO hearts, distinct from the classic cardiac remodeling program of fetal gene re-expression. Conclusions: We present genetic evidence that mitochondria play a protective role in CPVT. MCU-dependent Ca2+ uptake is crucial for preventing pathological cardiac remodeling in CPVT.http://www.sciencedirect.com/science/article/pii/S2772976124000333RyR2 leakCa2+-dependent cardiomyopathy |
| spellingShingle | Arpita Deb Brian D. Tow Jie Hao Branden L. Nguyen Valeria Gomez James A. Stewart, Jr Ashley J. Smuder Bjorn C. Knollmann Ying Wang Bin Liu Conditional ablation of MCU exacerbated cardiac pathology in a genetic arrhythmic model of CPVT Journal of Molecular and Cellular Cardiology Plus RyR2 leak Ca2+-dependent cardiomyopathy |
| title | Conditional ablation of MCU exacerbated cardiac pathology in a genetic arrhythmic model of CPVT |
| title_full | Conditional ablation of MCU exacerbated cardiac pathology in a genetic arrhythmic model of CPVT |
| title_fullStr | Conditional ablation of MCU exacerbated cardiac pathology in a genetic arrhythmic model of CPVT |
| title_full_unstemmed | Conditional ablation of MCU exacerbated cardiac pathology in a genetic arrhythmic model of CPVT |
| title_short | Conditional ablation of MCU exacerbated cardiac pathology in a genetic arrhythmic model of CPVT |
| title_sort | conditional ablation of mcu exacerbated cardiac pathology in a genetic arrhythmic model of cpvt |
| topic | RyR2 leak Ca2+-dependent cardiomyopathy |
| url | http://www.sciencedirect.com/science/article/pii/S2772976124000333 |
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