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Increased Intermembrane Space [Ca2+] Drives Mitochondrial Structural Damage in CPVT

Shanna Hamilton Orcid Logo, Radmila Terentyeva Orcid Logo, Roland Veress Orcid Logo, Fruzsina Perger, Zuzana Nichtova, Mark Bannister Orcid Logo, Jinxi Wang Orcid Logo, Sage Quiggle, Rachel Battershell Orcid Logo, Matthew W. Gorr Orcid Logo, Sandor Györke, Bum-Rak Choi Orcid Logo, Christopher George Orcid Logo, Andriy E. Belevych Orcid Logo, György Csordás Orcid Logo, Dmitry Terentyev Orcid Logo

Circulation Research

Swansea University Authors: Mark Bannister Orcid Logo, Christopher George Orcid Logo

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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...

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Published in: Circulation Research
ISSN: 0009-7330 1524-4571
Published: Ovid Technologies (Wolters Kluwer Health) 2025
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URI: https://cronfa.swan.ac.uk/Record/cronfa70572
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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(&#xB1;). 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.</abstract><type>Journal Article</type><journal>Circulation Research</journal><volume>0</volume><journalNumber/><paginationStart/><paginationEnd/><publisher>Ovid Technologies (Wolters Kluwer Health)</publisher><placeOfPublication/><isbnPrint/><isbnElectronic/><issnPrint>0009-7330</issnPrint><issnElectronic>1524-4571</issnElectronic><keywords/><publishedDay>23</publishedDay><publishedMonth>10</publishedMonth><publishedYear>2025</publishedYear><publishedDate>2025-10-23</publishedDate><doi>10.1161/circresaha.125.326841</doi><url/><notes/><college>COLLEGE NANME</college><department>Medical School</department><CollegeCode>COLLEGE CODE</CollegeCode><DepartmentCode>MEDS</DepartmentCode><institution>Swansea University</institution><apcterm>Another institution paid the OA fee</apcterm><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)</funders><projectreference/><lastEdited>2025-12-04T13:43:22.1057269</lastEdited><Created>2025-10-03T16:28:20.7330083</Created><path><level id="1">Faculty of Medicine, Health and Life Sciences</level><level id="2">Swansea University Medical School - Biomedical Science</level></path><authors><author><firstname>Shanna</firstname><surname>Hamilton</surname><orcid>0000-0003-1016-4706</orcid><order>1</order></author><author><firstname>Radmila</firstname><surname>Terentyeva</surname><orcid>0000-0002-0133-3515</orcid><order>2</order></author><author><firstname>Roland</firstname><surname>Veress</surname><orcid>0000-0001-8733-7228</orcid><order>3</order></author><author><firstname>Fruzsina</firstname><surname>Perger</surname><order>4</order></author><author><firstname>Zuzana</firstname><surname>Nichtova</surname><order>5</order></author><author><firstname>Mark</firstname><surname>Bannister</surname><orcid>0000-0002-0865-5912</orcid><order>6</order></author><author><firstname>Jinxi</firstname><surname>Wang</surname><orcid>0000-0002-7349-6153</orcid><order>7</order></author><author><firstname>Sage</firstname><surname>Quiggle</surname><order>8</order></author><author><firstname>Rachel</firstname><surname>Battershell</surname><orcid>0009-0002-5207-0388</orcid><order>9</order></author><author><firstname>Matthew W.</firstname><surname>Gorr</surname><orcid>0000-0001-7561-6481</orcid><order>10</order></author><author><firstname>Sandor</firstname><surname>Gy&#xF6;rke</surname><order>11</order></author><author><firstname>Bum-Rak</firstname><surname>Choi</surname><orcid>0000-0001-7319-3219</orcid><order>12</order></author><author><firstname>Christopher</firstname><surname>George</surname><orcid>0000-0001-9852-1135</orcid><order>13</order></author><author><firstname>Andriy E.</firstname><surname>Belevych</surname><orcid>0000-0002-1272-5784</orcid><order>14</order></author><author><firstname>Gy&#xF6;rgy</firstname><surname>Csord&#xE1;s</surname><orcid>0000-0003-3156-1460</orcid><order>15</order></author><author><firstname>Dmitry</firstname><surname>Terentyev</surname><orcid>0000-0002-9530-7384</orcid><order>16</order></author></authors><documents><document><filename>70572__35535__8870c7c8129842d1bdc45c72dc673fad.pdf</filename><originalFilename>hamilton-et-al-2025-increased-intermembrane-space-ca2-drives-mitochondrial-structural-damage-in-cpvt.pdf</originalFilename><uploaded>2025-11-03T09:58:00.1145485</uploaded><type>Output</type><contentLength>5672119</contentLength><contentType>application/pdf</contentType><version>Proof</version><cronfaStatus>true</cronfaStatus><documentNotes>&#xA9; 2025 The Authors. This is an open access article under the terms of the Creative Commons Attribution Non-Commercial-NoDerivs License.</documentNotes><copyrightCorrect>true</copyrightCorrect><language>eng</language><licence>https://creativecommons.org/licenses/by-nc-nd/4.0/</licence></document></documents><OutputDurs/></rfc1807>
spelling 2025-12-04T13:43:22.1057269 v2 70572 2025-10-03 Increased Intermembrane Space [Ca2+] Drives Mitochondrial Structural Damage in CPVT cd153d7ad8b74a44d0401211d66d1e20 0000-0002-0865-5912 Mark Bannister Mark Bannister true false a2e211f7bd379c81e9c393637803a0a0 0000-0001-9852-1135 Christopher George Christopher George true false 2025-10-03 MEDS 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. Journal Article Circulation Research 0 Ovid Technologies (Wolters Kluwer Health) 0009-7330 1524-4571 23 10 2025 2025-10-23 10.1161/circresaha.125.326841 COLLEGE NANME Medical School COLLEGE CODE MEDS Swansea University Another institution paid the OA fee 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) 2025-12-04T13:43:22.1057269 2025-10-03T16:28:20.7330083 Faculty of Medicine, Health and Life Sciences Swansea University Medical School - Biomedical Science Shanna Hamilton 0000-0003-1016-4706 1 Radmila Terentyeva 0000-0002-0133-3515 2 Roland Veress 0000-0001-8733-7228 3 Fruzsina Perger 4 Zuzana Nichtova 5 Mark Bannister 0000-0002-0865-5912 6 Jinxi Wang 0000-0002-7349-6153 7 Sage Quiggle 8 Rachel Battershell 0009-0002-5207-0388 9 Matthew W. Gorr 0000-0001-7561-6481 10 Sandor Györke 11 Bum-Rak Choi 0000-0001-7319-3219 12 Christopher George 0000-0001-9852-1135 13 Andriy E. Belevych 0000-0002-1272-5784 14 György Csordás 0000-0003-3156-1460 15 Dmitry Terentyev 0000-0002-9530-7384 16 70572__35535__8870c7c8129842d1bdc45c72dc673fad.pdf hamilton-et-al-2025-increased-intermembrane-space-ca2-drives-mitochondrial-structural-damage-in-cpvt.pdf 2025-11-03T09:58:00.1145485 Output 5672119 application/pdf Proof true © 2025 The Authors. This is an open access article under the terms of the Creative Commons Attribution Non-Commercial-NoDerivs License. true eng https://creativecommons.org/licenses/by-nc-nd/4.0/
title Increased Intermembrane Space [Ca2+] Drives Mitochondrial Structural Damage in CPVT
spellingShingle Increased Intermembrane Space [Ca2+] Drives Mitochondrial Structural Damage in CPVT
Mark Bannister
Christopher George
title_short Increased Intermembrane Space [Ca2+] Drives Mitochondrial Structural Damage in CPVT
title_full Increased Intermembrane Space [Ca2+] Drives Mitochondrial Structural Damage in CPVT
title_fullStr Increased Intermembrane Space [Ca2+] Drives Mitochondrial Structural Damage in CPVT
title_full_unstemmed Increased Intermembrane Space [Ca2+] Drives Mitochondrial Structural Damage in CPVT
title_sort Increased Intermembrane Space [Ca2+] Drives Mitochondrial Structural Damage in CPVT
author_id_str_mv cd153d7ad8b74a44d0401211d66d1e20
a2e211f7bd379c81e9c393637803a0a0
author_id_fullname_str_mv cd153d7ad8b74a44d0401211d66d1e20_***_Mark Bannister
a2e211f7bd379c81e9c393637803a0a0_***_Christopher George
author Mark Bannister
Christopher George
author2 Shanna Hamilton
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
format Journal article
container_title Circulation Research
container_volume 0
publishDate 2025
institution Swansea University
issn 0009-7330
1524-4571
doi_str_mv 10.1161/circresaha.125.326841
publisher Ovid Technologies (Wolters Kluwer Health)
college_str Faculty of Medicine, Health and Life Sciences
hierarchytype
hierarchy_top_id facultyofmedicinehealthandlifesciences
hierarchy_top_title Faculty of Medicine, Health and Life Sciences
hierarchy_parent_id facultyofmedicinehealthandlifesciences
hierarchy_parent_title Faculty of Medicine, Health and Life Sciences
department_str Swansea University Medical School - Biomedical Science{{{_:::_}}}Faculty of Medicine, Health and Life Sciences{{{_:::_}}}Swansea University Medical School - Biomedical Science
document_store_str 1
active_str 0
description 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.
published_date 2025-10-23T05:31:10Z
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score 11.444473

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