Increased Intermembrane Space [Ca <sup>2+</sup> ] Drives Mitochondrial Structural Damage in CPVT
Our data suggest that RyR2 hyperactivity contributes to mitochondrial structural damage by promoting an increase in IMS-[Ca<sup>2+</sup>], 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.
Authors
- Sándor Györke (ORCID: https://orcid.org/0000-0002-0821-1983)
- Matthew W. Gorr (ORCID: https://orcid.org/0000-0001-7561-6481)
- Bum‐Rak Choi (ORCID: https://orcid.org/0000-0001-7319-3219)
- Radmila Terentyeva (ORCID: https://orcid.org/0000-0002-0133-3515)
- Shanna Hamilton (ORCID: https://orcid.org/0000-0003-1016-4706)
- Mark L. Bannister (ORCID: https://orcid.org/0000-0002-0865-5912)
- Christopher H. George (ORCID: https://orcid.org/0000-0001-9852-1135)
- Fruzsina Perger
- Zuzana Nichtová (ORCID: https://orcid.org/0000-0001-7358-3268)
- Andriy E. Belevych (ORCID: https://orcid.org/0000-0002-1272-5784)
- György Csordás (ORCID: https://orcid.org/0000-0003-3156-1460)
- Sage Quiggle
- Jinxi Wang (ORCID: https://orcid.org/0000-0002-7349-6153)
- Dmitry Terentyev (ORCID: https://orcid.org/0000-0002-9530-7384)
- Roland Veress (ORCID: https://orcid.org/0000-0001-8733-7228)
- Rachel Battershell
Institutions
- University of Arizona (US)
- Thomas Jefferson University (US)
- Brown University (US)
- The Ohio State University Wexner Medical Center (US)
- Swansea University (GB)
- ABB (United States) (US)
- The Ohio State University (US)
Publication Details
- Journal
- Circulation Research
- Published
- 2025-10-23
- DOI
- https://doi.org/10.1161/circresaha.125.326841
- Citations
- 2
- Primary Topic
- Mitochondrial Function and Pathology
- Type
- article
- Field-Weighted Citation Impact
- 1.61