Mitochondrial ferritin inhibition aggravates pacing-induced ventricular arrhythmias after myocardial infarction by promoting cardiomyocyte ferroptosis.

BACKGROUND

Post-myocardial infarction ventricular arrhythmias are a leading cause of sudden cardiac death (SCD) following acute myocardial infarction worldwide. Emerging evidence suggests that ferroptosis, an iron-dependent form of cell death, plays a significant role in myocardial infarction damage. While mitochondrial ferritin (FtMt) is known to encapsulate harmful ferrous ions within mitochondria, its role in the development of post-myocardial infarction ventricular arrhythmias (post-MI VAs) is not well understood.

OBJECTIVE

This study aimed to clarify the role and mechanisms by which FtMt-mediated ferroptosis influences susceptibility to post-MI VAs.

METHODS

Mice were subjected to permanent ligation of the left anterior descending artery (LAD) to induce myocardial infarction (MI), followed by intracardiac electrophysiological studies to evaluate their vulnerability to post-MI VAs. Patch-clamp recordings and confocal Ca2+ imaging provided data on neonatal rat ventricular myocytes (NRVMs). We utilized DCFH-DA staining, transmission electron microscopy, and Seahorse analysis to examine the mitochondrial bioenergetics and oxidative phosphorylation in NRVMs.

RESULTS

Ferroptosis was activated in mice post-MI. Inhibiting ferroptosis enhanced cardiac function and reduced the incidence of post-MI VAs. Hypoxia led to electrophysiological dysregulation in NRVMs, which was exacerbated by FtMt inhibition. Specifically, FtMt inhibition under hypoxic conditions further impaired mitochondrial bioenergetics and oxidative phosphorylation, promoting ferroptosis in NRVMs.

CONCLUSION

FtMt plays a crucial protective function in MI by limiting infarct size, decreasing the frequency of ventricular arrhythmias, and inhibiting ferroptosis both in vivo and in vitro. These results suggest that FtMt may be a viable therapeutic target for treating MI.