Succinate links metabolism to atrial fibrillation via multiple mechanisms: the SUCNR1/PKA/ THRα/IP3R1 axis governs calcium dysregulation, electrophysiological remodeling, and inflammatory activation

Background Atrial fibrillation (AF), the most common arrhythmia, is closely associated with metabolic disorders like obesity, diabetes and hyperthyroidism, while the precise mechanisms remain unclear. Succinate, a key TCA cycle intermediate, accumulates during metabolic stress and energy mismatch. This excess disrupts homeostasis and alters the tissue microenvironment via its receptor SUCNR1. Our preliminary data show elevated circulating succinate in AF patients, correlating with atrial dilation. Purpose This study examines if succinate acts as a metabolic link between metabolic disorders and AF pathogenesis, aiming to elucidate its downstream effects on cellular signaling, atrial electrophysiological remodeling, and immune-inflammatory cascades. This provides novel mechanistic insights and identifies potential therapeutic targets for metabolism-driven AF. Methods To confirm that metabolic dysfunction elevates circulating succinate, we measured plasma succinate in high-fat diet rats. A succinate-supplemented rat model was used to assess AF susceptibility and atrial remodeling via optical mapping, echocardiography, and histology. We further isolated primary atrial myocytes from suckling rats. Using g gene knockdown and overexpression strategies, calcium imaging, transcriptomics, and bioinformatic network analysis, we investigated the downstream mechanisms mediated by succinate via SUCNR1, including disrupted calcium signaling, altered ion channel function, and inflammatory activation. Results Obese rats showed elevated circulating succinate, and succinate intervention increased both AF inducibility and duration. This was accompanied by marked electrical remodeling (shortened effective refractory period), disrupted calcium homeostasis, and structural changes, including atrial enlargement and exacerbated fibrosis. Mechanistically, succinate acts via the SUCNR1 to inhibit protein kinase A (PKA) activity, which downregulates thyroid hormone receptor alpha (THRα) expression. This pathway leads to elevated inositol 1,4,5-trisphosphate receptor 1 (IP3R1) levels, triggering sarcoplasmic reticulum calcium leakage and cytoplasmic Ca²⁺ overload. Resultant activation of Ca²⁺ calmodulin-dependent protein kinase II (CaMKII) alters Kv1.5 potassium channel expression, driving electrical remodeling. Simultaneously, elevated Ca²⁺ activates interferon regulatory factor 7 (IRF7) via CaMKII, upregulating inflammatory markers and shifting myocytes toward a pro-inflammatory recruitment phenotype. Conclusions This study reveals succinate as a key mediator in metabolism-related AF, driving atrial remodeling and heightened AF susceptibility via SUCNR1-activated dual pathways. It provides a novel framework for the disease's pathogenesis and identifies plasma succinate as a potential stratification and predictive biomarker. Furthermore, SUCNR1 and downstream molecules represent candidate therapeutic targets.mechanism