Journal article
Increased Intermembrane Space [Ca 2+ ] Drives Mitochondrial Structural Damage in CPVT
Circulation research, Vol.137(12), pp.1385-1403
12/05/2025
DOI: 10.1161/CIRCRESAHA.125.326841
PMCID: PMC12680285
PMID: 41127903
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(Ser2336Leu)(+/-). 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.
Details
- Title: Subtitle
- Increased Intermembrane Space [Ca 2+ ] Drives Mitochondrial Structural Damage in CPVT
- Creators
- Shanna Hamilton - The Ohio State UniversityRadmila Terentyeva - The Ohio State UniversityRoland Veress - The Ohio State UniversityFruzsina Perger - The Ohio State UniversityZuzana Nichtova - Thomas Jefferson UniversityMark Bannister - Swansea UniversityJinxi Wang - University of IowaSage Quiggle - University of ArizonaRachel Battershell - University of ArizonaMatthew W Gorr - The Ohio State UniversitySandor Györke - The Ohio State UniversityBum-Rak Choi - Brown UniversityChristopher H George - Swansea UniversityAndriy E Belevych - The Ohio State UniversityGyörgy Csordás - Thomas Jefferson UniversityDmitry Terentyev - The Ohio State University
- Resource Type
- Journal article
- Publication Details
- Circulation research, Vol.137(12), pp.1385-1403
- DOI
- 10.1161/CIRCRESAHA.125.326841
- PMID
- 41127903
- PMCID
- PMC12680285
- NLM abbreviation
- Circ Res
- ISSN
- 0009-7330
- eISSN
- 1524-4571
- Publisher
- American Heart Association; PHILADELPHIA
- Grant note
- National Institutes of Health (NIH) National Heart, Lung and Blood Institute (NHLBI): R00HL155492 NIH NHLBI: R01HL167963, R01HL063043, R01HL074045, R01HL138579, R01HL122124, R01HL142864, R01HL166604, R01HL142588, R03TR004471 NIH National Institute of Diabetes and Digestive and Kidney Diseases: R01DK125897 American Heart Association (AHA) Postdoctoral Fellowship: 916348 AHA Transformational Project Award: 24TPA1293486, 25TPA1468455 Harold S. Geneen Charitable Trust Awards Program for Coronary Heart Disease ResearchUniversity of Arizona Sarver Heart CenterBritish Heart Foundation: RG/15/6/31436 Welsh Government Infrastructure Award
This work was supported by grants from the National Institutes of Health (NIH) National Heart, Lung, and Blood Institute (NHLBI) R00HL155492 (to S. Hamilton), NIH NHLBI R01HL167963 (to M.W. Gorr) NIH NHLBI R01HL063043, NIH NHLBI R01HL074045, and NIH NHLBI R01HL138579 (to S. Gyoerke), NIH NHLBI R01HL122124, NIH NHLBI R01HL142864, and NIH National Institute of Diabetes and Digestive and Kidney Diseases R01DK125897 (to G. Csordas), NIH NHLBI R01HL166604, NIH NHLBI R01HL142588, and NIH NHLBI R03TR004471 (to D. Terentyev), the American Heart Association (AHA) Postdoctoral Fellowship 916348 (to R. Veress), the AHA Transformational Project Award 24TPA1293486 (to D. Terentyev) and 25TPA1468455 (https://doi.org/10.58275/AHA.25TPA1468455.pc.gr.233968; to S. Hamilton), the Harold S. Geneen Charitable Trust Awards Program for Coronary Heart Disease Research (to S. Hamilton), the University of Arizona Sarver Heart Center (to S. Hamilton), the British Heart Foundation RG/15/6/31436 (to C.H. George and M. Bannister), and a Welsh Government Infrastructure Award (to C. George and M. Bannister).
- Language
- English
- Electronic publication date
- 10/23/2025
- Date published
- 12/05/2025
- Academic Unit
- Internal Medicine
- Record Identifier
- 9985019147502771
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