Logo

American Heart Association

  17
  0


Final ID: Wed121

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

Abstract Body: 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.
  • Yoon, Jin-young  ( The University of Iowa , Iowa City , Iowa , United States )
  • Chen, Biyi  ( The University of Iowa , Iowa City , Iowa , United States )
  • Song, Long-sheng  ( The University of Iowa , Iowa City , Iowa , United States )
  • London, Barry  ( The University of Iowa , Iowa City , Iowa , United States )
  • Author Disclosures:
Meeting Info:

Basic Cardiovascular Sciences 2026

2026

Boston, Massachusetts

Session Info:

Poster Session 3

Wednesday, 07/15/2026 , 04:30PM - 07:00PM

Poster Session and Reception

More abstracts on this topic:
Associations of Long-Chain and Very-Long-Chain Saturated Fatty Acids with Outcomes of Sudden Cardiac Arrest

Li Jason, Brody Jennifer, Wiggins Kerri, Swenson Brenton, Jensen Paul, Bockus Lee, Lemaitre Rozenn, Sootedehnia Nona

Acetylation of Mitochondrial Cyclophilin D Increases vascular Oxidative Stress, Induces Glycolitic Switch, Promotes Endothelial Dysfunction and Hypertension

Dikalov Sergey, Sack Michael, Dikalova Anna, Fehrenbach Daniel, Mayorov Vladimir, Panov Alexander, Ao Mingfang, Lantier Louise, Amarnath Venkataraman, Lopez Marcos, Billings Frederic

More abstracts from these authors:
SIRTUIN5 Modulates Na+/Ca2+ Handling Via Oxidative Stress Dependent Manner In Mouse Heart

Choi Hannah, Chen Biyi, Song Long-sheng, Lombard David, Yoon Jin-young, London Barry

SIRT5 Dysfunction Evokes Arrhythmias and Na+ and Ca2+ Mishandling in mouse heart

Yoon Jin-young, Choi Hannah, Chen Biyi, Song Long-sheng, London Barry

You have to be authorized to contact abstract author. Please, Login
Not Available