Abstract Body (Do not enter title and authors here): Atrial fibrillation (AF), the most common sustained cardiac arrhythmia, is strongly associated with aging, structural heart disease, and heart failure, yet its molecular mechanisms remain poorly understood, limiting effective therapies. Recent metabolomic and proteomic studies have revealed altered expression of metabolic pathway-related molecules in both human and experimental AF. Among them, adenosine monophosphate-activated protein kinase (AMPK), a serine-threonine kinase and metabolic sensor, has emerged as a potential therapeutic target for restoring energy homeostasis and promoting cardiomyocyte survival. Programmed cell death 5 (PDCD5), known for its role in apoptosis, is also implicated in cardiac pathology. However, its function in AF and potential interaction with AMPK signaling remain unexplored.
This study aims to determine whether PDCD5 regulates AMPK phosphorylation and whether this regulation contributes to AF pathogenesis, thereby identifying a novel molecular mechanism and therapeutic target for AF.
To investigate the role of PDCD5 in cardiac electrophysiology, we employed PDCD5 knockout (KO) mice. Compared to wild-type (WT) controls, PDCD5 KO mice displayed prolonged QT and QRS intervals and showed significantly higher AF inducibility following rapid atrial pacing. Histological analysis revealed increased atrial fibrosis in KO mice. Co-immunoprecipitation assays confirmed a direct interaction between PDCD5 and AMPK. Moreover, PDCD5 knockdown impaired AMPK activation, as shown by reduced AMPK phosphorylation. Metformin treatment failed to restore AMPK phosphorylation in the absence of PDCD5. Consistently, metformin administration failed to reduce AF susceptibility in PDCD5 KO mice, suggesting a loss of AMPK-mediated protective effects in the absence of PDCD5. In human iPSC-derived cardiomyocytes, PDCD5 knockdown led to reduced calcium transient amplitude and delayed calcium reuptake, in non-pacing condition. Under tachypacing conditions, metformin restored calcium homeostasis in control cells but not in PDCD5-deficient cells.
These findings demonstrate that PDCD5 plays a critical role in maintaining atrial electrical and calcium homeostasis through an AMPK-dependent mechanism. PDCD5 is necessary for proper AMPK phosphorylation and cardioprotective signaling, and its deficiency contributes to increased AF vulnerability. Targeting the PDCD5–AMPK axis may offer a novel therapeutic strategy for the prevention and treatment of AF.