Mitochondrial dysfunction drives ZBP1-mediated PANoptosis to increase the susceptibility of heart failure with preserved ejection fraction-associated atrial fibrillation

Introduction

Heart failure with preserved ejection fraction (HFpEF) is frequently complicated by atrial fibrillation (AF), but underlying molecular mechanisms remain poorly defined. Mitochondrial dysfunction drives ZBP1-mediated PANoptosis is crucial in understanding the progression of HFpEF-associated AF and exploring novel therapeutic avenues.

Objectives

This study investigates the Z-DNA binding protein 1 (ZBP1) as a critical mediator linking mitochondrial dysfunction with PANoptosis by sensing mitochondrial Z-DNA (mtZ-DNA) in HFpEF-associated AF.

Methods

Variety of in vivo and in vitro experimental approaches were employed, majorly including HFpEF mouse model establishment, Histological staining, RNA sequencing, Western blotting, co-immunoprecipitation, Transmission electron microscopy (TEM) and confocal imaging.

Results

In a “Two-hit” HFpEF mouse model, we observed increased AF susceptibility with prolonged modeling. Additionally, bioinformatics analysis and in vivo and in vitro studies highlighted progressive ZBP1-mediated PANoptosis accompanied by mitochondrial dysfunction in HFpEF atria. Inflammation and cardiomyocyte loss caused by PANoptosis contributed to atrial remodeling and AF. Also, NAD⁺ depletion in HFpEF cardiomyocytes downregulated mitochondrial topoisomerases (TOP3A and TOP1MT) and mitochondrial DNA (mtDNA) stress, promoting mtZ-DNA formation. ZBP1 sensed and stabilized Z-DNA via its Zα1 domain and recruited Receptor-Interacting Protein Kinases (RIPKs) and Caspase8 to assemble the PANoptosome and initiate PANoptosis. Silencing Zbp1 alleviated atrial remodeling and reduced AF vulnerability. Moreover, NAD⁺ supplementation suppressed Z-DNA formation and ZBP1 activation by improving mitochondrial dysfunction. These findings identify ZBP1 as a molecular bridge between mitochondrial dysfunction and PANoptosis, highlighting its central role in HFpEF-associated AF pathogenesis. Targeting this axis may provide a promising therapeutic strategy combatting AF in HFpEF.

Conclusions

These findings identify ZBP1 as a molecular bridge between mitochondrial dysfunction and PANoptosis by sensing mitochondrial Z-DNA, highlighting its central role in HFpEF-associated AF pathogenesis. Targeting this axis may provide a promising therapeutic strategy combatting AF in HFpEF.