Logo image
Back
Abstract Wed121: Mitochondrial ROS-Driven Late INa Promotes Ca2+ Overload and Triggered Arrhythmias in SIRT5 Loss-of-Function Mouse Heart
Abstract   Peer reviewed

Abstract Wed121: Mitochondrial ROS-Driven Late INa Promotes Ca2+ Overload and Triggered Arrhythmias in SIRT5 Loss-of-Function Mouse Heart

Jin-Young Yoon, Biyi Chen, Long-Sheng Song and Barry London
Circulation research, Vol.139(Suppl_1), pp.AWed121-AWed121
07/17/2026
DOI: 10.1161/res.139.suppl_1.Wed121

View Online

Abstract

Background: SIRT5, a mitochondrial NAD+-dependent deACYLase, is implicated in arrhythmia through hypomorphic P114T variants identified in small families with sudden cardiac death. Cardiac Na+ current (INa), predominantly through NaV1.5, governs cardiac action potential. We previously demonstrated elevated mitochondrial reactive oxygen species (ROS) and late INa in P114T-SIRT5 hearts. Hypothesis: ROS-driven late INa augmentation drives Na+ and Ca2+ overload, triggering DADs and arrhythmias in SIRT5-loss-of-function hearts under adrenergic stress. Aim: To define the arrhythmia substrate downstream of mitochondrial ROS-late INa dysregulation in P114T-Sirt5 knock-in and Sirt5-/- mice. Methods: Patch-clamp in isolated ventricular cardiomyocytes, confocal Ca2+ spark/wave imaging, in vivo epinephrine/caffeine ECG challenge, co-immunoprecipitation for NaV1.5 ACYLation, and cardiac RNA-seq. Results: Mitochondrial ROS scavenger mitoTEMPO normalized late INa in P114T cardiomyocytes (Fig. A), establishing causal ROS→late INa coupling, while antioxidant GSH reversed spontaneous Ca2+ waves and triggered activity. Sirt5−/− hearts showed elevated Ca2+ spark frequency (Fig. B) and isoproterenol-induced DADs and triggered activity. In vivo, P114T mice exhibited genotype-dependent arrhythmias under epinephrine/caffeine challenge, including ventricular tachycardia (VT; Fig. C). At the molecular level, the Na+/Ca2+ exchanger NCX1 expression was upregulated, and NaV1.5 succinylation and acetylation were elevated without changes in protein expression, consistent with impaired SIRT5 deACYLase activity. RNA-seq identified 86 differentially expressed genes including Scn3b and Cybrd1. Conclusion: SIRT5 loss-of-function hearts exhibit mitochondrial ROS-driven late INa augmentation, Ca2+ mishandling, and arrhythmias under stress. The mechanisms linking SIRT5 loss to late INa elevation and proarrhythmic Na+ and Ca2+ overload warrant further investigation.
 Oxidative Stress Sodium channel Calcium Sudden cardiac death Myocyte electrophysiology

Details

Metrics

1 Record Views
Logo image