Connexin 43 deficiency leads to ventricular arrhythmias by reprogramming proline metabolism

Connexin 43 (Cx43) is the predominant connexin in working myocardium. Its expression decreases in various cardiovascular diseases, and accompanied by ventricular arrhythmias (VAs). However, molecular mechanisms underlying increased arrhythmogenesis remained unclear. Here we established iPSC-derived cardiomyocytes (iPSC-CMs) and mouse models of Gja1 KO with proarrhythmic activity and disrupted proline metabolism. Mechanistically, Cx43 interacts with sodium-coupled neutral amino acid transporter 2 (SNAT2) where Gja1 KO reduces expression of SNAT2, leading to decreased proline and disrupted proline metabolism. Proline cycle in mitochondria preserves energetic/redox balance and exerts cardioprotective effects. Elevated reactive oxygen species (ROS) caused by disrupted proline metabolism leads to abnormal calcium handing and arrhythmia events. Taken together, the absence of Cx43 could facilitate the development of arrhythmias through reprogramming proline metabolism independent of reentry mechanisms, and indicated that molecular pathway of Cx43- SNAT2- ROS plays an essential role in maintaining normal cardiac rhythm.