Abstract

BACKGROUND Atrial fibrillation (AF) is characterized by severe structural and electrical remodeling that is driven in part by calcium (Ca2+) mishandling and mitochondrial dysfunction. While programmed cell death 4 (PDCD4) has been implicated in several cardiovascular pathologies, its precise role in AF remains unclear. METHODS in vivo AF mouse models (Ang II infusion combined with burst pacing) and in vitro models using rapidly paced AC16 cardiomyocytes were established. Atrial electrophysiology, fibrosis, mitochondrial dynamics, reactive oxygen species (ROS) production, mitochondrial membrane potential, and Ca2+ transients were evaluated using multi-electrode recordings, histological staining, transmission electron microscopy, fluorescence imaging, flow cytometry, and calcium imaging. RESULTS PDCD4 was significantly upregulated in both AF atrial tissues and paced cardiomyocytes. In vivo, PDCD4 overexpression exacerbated AF inducibility, prolonged AF duration, shortened the atrial effective refractory period (AERP), and aggravated atrial fibrosis. Mechanistically, PDCD4 promoted excessive mitochondrial fission, as evidenced by upregulated DRP1 and FIS1 and downregulated MFN1/2 and OPA1, resulting in mitochondrial fragmentation, ROS overproduction, and loss of membrane potential. This oxidative stress subsequently triggered hyperactivation of the CaM/CaMKII signaling pathway, leading to intracellular Ca2+ overload and prolonged excitation-contraction coupling. Notably, pharmacological blockade of mitochondrial fission using Mdivi-1 blunted ROS production, suppressed CaMKII hyperactivation, and reversed PDCD4-induced atrial remodeling and calcium dyshomeostasis. CONCLUSION