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Increased Intermembrane Space [Ca2+] Drives Mitochondrial Structural Damage in CPVT
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Radmila Terentyeva ,
Roland Veress ,
Fruzsina Perger,
Zuzana Nichtova,
Mark Bannister ,
Jinxi Wang ,
Sage Quiggle,
Rachel Battershell ,
Matthew W. Gorr ,
Sandor Györke,
Bum-Rak Choi ,
Christopher George ,
Andriy E. Belevych ,
György Csordás ,
Dmitry Terentyev
Circulation Research
Swansea University Authors:
Mark Bannister , Christopher George
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DOI (Published version): 10.1161/circresaha.125.326841
Abstract
BACKGROUND:Mitochondrial dysfunction caused by abnormally high RyR2 (ryanodine receptor) activity is a common finding in cardiovascular diseases. Mechanisms linking RyR2 gain of function with mitochondrial remodeling remain elusive. We hypothesized that RyR2 hyperactivity in cardiac disease increase...
| Published in: | Circulation Research |
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| ISSN: | 0009-7330 1524-4571 |
| Published: |
Ovid Technologies (Wolters Kluwer Health)
2025
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| Online Access: |
Check full text
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| URI: | https://cronfa.swan.ac.uk/Record/cronfa70572 |
| Abstract: |
BACKGROUND:Mitochondrial dysfunction caused by abnormally high RyR2 (ryanodine receptor) activity is a common finding in cardiovascular diseases. Mechanisms linking RyR2 gain of function with mitochondrial remodeling remain elusive. We hypothesized that RyR2 hyperactivity in cardiac disease increases [Ca2+] in the mitochondrial intermembrane space (IMS) and activates the Ca2+-sensitive protease calpain, driving remodeling of mitochondrial cristae architecture through cleavage of structural protein OPA1 (optic atrophy protein 1).METHODS:We generated a highly arrhythmogenic rat model of catecholaminergic polymorphic ventricular tachycardia, induced by RyR2 gain-of-function mutation S2236L(±). We created a new biosensor to measure IMS-[Ca2+] in adult cardiomyocytes with intact Ca2+ cycling. We used ex vivo whole heart optical mapping, confocal and electron microscopy, as well as in vivo/in vitro gene editing techniques to test the effects of calpain in the IMS.RESULTS:We found altered mitochondrial cristae structure, increased IMS-[Ca2+], reduced OPA1 expression, and augmented mito-reactive oxygen species emission in catecholaminergic polymorphic ventricular tachycardia myocytes. We show that calpain-mediated OPA1 cleavage led to disrupted cristae organization and, thereby, decreased electron transport chain supercomplex assembly, resulting in accelerated reactive oxygen species production. Genetic inhibition of calpain activity in IMS reversed mitochondria structural defects in catecholaminergic polymorphic ventricular tachycardia myocytes and reduced arrhythmic burden in ex vivo optically mapped hearts.CONCLUSIONS:Our data suggest that RyR2 hyperactivity contributes to mitochondrial structural damage by promoting an increase in IMS-[Ca2+], sufficient to activate IMS-residing calpain. Calpain activation leads to proteolysis of OPA1 and cristae widening, thereby decreasing assembly of electron transport chain components into supercomplexes. Consequently, excessive mito-reactive oxygen species release critically contributes to RyR2 hyperactivation and ventricular tachyarrhythmia. Our new findings suggest that targeting IMS calpain may be beneficial in patients at risk for sudden cardiac death. |
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| College: |
Faculty of Medicine, Health and Life Sciences |
| Funders: |
British Heart Foundation (BHF; RG/15/6/31436), Health and Care Research Wales; National Heart Lung and Blood Institute (NHLBI), American Heart Association (AHA), National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) |