Atrial-specific LKB1 knockout mice and validation in human atrial tissue reveal that lysine propionylation of OXCT1 is associated with atrial fibrillation

Abstract

Abstract Atrial fibrillation (AF), the most prevalent clinical arrhythmia, imposes a major global health burden through elevated risks of stroke, heart failure, and mortality. Lysine propionylation (Kpr) is mainly involved in metabolic regulation and plays an important role in cardiac pathophysiology. However, the specific role and mechanism of Kpr in AF remain unclear. Here we show that significantly increased Kpr levels of 3-oxoacid CoA-transferase 1 (OXCT1) at lysine-296 (K296) are found both in atrial tissues of AF mice induced by atrial-specific LKB1 knockout and in right atrial tissues of patients with postoperative AF (POAF) after coronary artery bypass grafting (CABG). We find that propionylation is associated with reduced the enzyme activity of OXCT1 and disrupts its interaction with acetyl-CoA acetyltransferase 1 (ACAT1), accompanied by decreased ACAT1 protein expression. Furthermore, these changes are associated with reduced the production of succinate and adenosine triphosphate (ATP), resulting in an imbalance of mitochondrial energy metabolism, as well as increased intracellular ROS and mitochondrial ROS (mitoROS), suggesting enhanced oxidative stress. Our results reveal that elevated propionylation of OXCT1 at K296 may represent a regulatory mechanism contributing to metabolic and oxidative stress in AF, providing new insights into the etiology of AF and potential therapeutic targets.