Succinate predisposes mice to atrial fibrillation by impairing mitochondrial function via SUCNR1/AMPK axis.

Atrial fibrillation (AF), a major public health concern, is associated with high rates of death and disability. Mitochondrial dysfunction has emerged as a key contributor to the pathophysiology of AF. Succinate, an essential Krebs cycle metabolite, is often elevated in the circulation of patients at risk for AF. However, its exact role in AF pathogenesis is still not well understood. To explore the association linking succinate overload and AF, we first established AF-susceptible mouse models of obesity and diabetes, confirming that circulating succinate levels were significantly elevated in these AF-prone mice. Next, we assessed AF vulnerability and atrial remodeling in succinate-treated mice (2 %/5 % for 7 weeks) or isolated primary atrial cells (0.5 mM for 24 h). Our results demonstrated that succinate overload increased AF susceptibility in mice and triggered adverse atrial remodeling, characterized by left atrial dilation, connexins lateralization, ion channel disturbances, and fibrosis. Moreover, succinate compromised atrial mitochondrial structure, leading to increased oxidative stress. Mechanistically, succinate overload upregulated the expression of its cognate receptor SUCNR1 (succinate receptor 1) and decreased AMPK (AMP-activated protein kinase) phosphorylation both in vitro and in vivo. AICAR (AMPK activator) maintained mitochondrial health to mitigate remodeling in succinate-exposed cells and prevented succinate-induced AF in obese and diabetic mice. In conclusion, succinate overload enhances AF vulnerability and atrial remodeling by impairing AMPK signaling and mitochondrial function. Succinate, therefore, represents an underappreciated contributor to AF pathogenesis and a potential biomarker.