Connexin43 Deficiency Leads to Ventricular Arrhythmias by Reprogramming Proline Metabolism

Ventricular arrhythmias (VAs) as life-threatening heart rhythm disorders, reduced connexin43 (Cx43) is one of the mechanisms of VAs. Cx43 is the predominant ventricular gap junction protein essential for cardiac electrical conduction; the absence in the mouse heart results in sudden arrhythmic death. However, the mechanism linking Cx43 downregulation and VA formation remains unclear. Here it is aimed to elucidate the molecular mechanism by which Cx43 deficiency leads to VAs using Cx43 knockout (Cx43-KO) induced pluripotent stem-derived cardiomyocytes and cardiac-specific conditional Cx43-KO (Cx43-cKO) mice. It is shown that Cx43-KO induced arrhythmic phenotype and decreased proline content both in vitro and in vivo. Mechanistically, Cx43 interacts with the amino acid transporter SNAT2 (sodium-dependent neutral amino acid transporter). Cx43 deficiency reduces SNAT2 expression, impairing proline transport and metabolism. This disruption leads to mitochondrial dysfunction, oxidative stress, abnormal calcium handling, and arrhythmias. Exogenous proline supplementation rescued the arrhythmic phenotype in Cx43-cKO mice by restoring metabolic balance. In conclusion, it is suggested that Cx43 deficiency leads to VAs through SNAT2-mediated proline metabolic reprogramming. Targeting proline metabolism may therefore offer novel therapeutic strategies for VAs.