Project description:Lysine propionylation modification (Kpr) plays an important role in the pathogenesis of several cardiovascular diseases, but the role of Kpr in postoperative atrial fibrillation (POAF) is unclear. Here, we established an atlas of proteomics and propionylation proteomics in the atrial appendage tissues from 28 aging CABG patients, exploring the role of Kpr proteins in the occurrence of POAF. The Kpr of ALDH6A1 was most significantly increased on Lys113 (2.25 folds). The activity of ALDH6A1 increased due to higher binding energy of propionylated ALDH6A1 and NAD+, causing an increase in NADH levels in cells and triggering abnormal energy metabolism. Furthermore, the increase in NADH levels triggered the accumulation of reactive oxygen species, which may cause oxidative stress and cardiac electrical remodeling, resulting in the development of AF. This study reveals the important role of ALDH6A1-NADH pathway in POAF, and provides new insights for exploring the pathogenesis of POAF in CABG.
Project description: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) were 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 found that propionylation greatly reduced the enzyme activity of OXCT1 and inhibited its interaction with acetyl-CoA acetyltransferase 1 (ACAT1), leading to decreased ACAT1 protein expression. Furthermore, on the one hand, these changes reduced the production of succinate and adenosine triphosphate (ATP), resulting in an imbalance of mitochondrial energy metabolism, and on the other hand, increased the production of intracellular ROS and mitochondrial ROS (mitoROS), triggering oxidative stress. Our results reveal that elevated propionylation of OXCT1 at K296 is a crucial molecular mechanism underlying AF, providing new insights into the etiology of AF and potential therapeutic targets.
