Fig. 2

Hypothesized mechanism of SARA-Smurf2 associated Connexin43/45 endocytosis and degradation via aberration of TGF-β signaling may critically cause the mosaic loss of electroconductive gap-junction protein Connexin43/45 in aging men with mLOY. An anchoring protein SARA (Smad anchor for receptor activation) binds to TGF-β receptors and activate ubiquitylation via Smurf2 (Smad ubiquitination regulatory factor-2). The Clathrin-coated early Connexin43/45 endosome then combines with cytoplasmic lysosome generated by ER-Golgi complex to form the late endosome, in which the gap-junction protein Connexin43/45 undergo degradation. This results in disassembly of gap-junctions, which could result in impaired cardiac conduction and subsequent cardiac arrhythmia. ER, endoreticulum; GRPs, Gene regulatory proteins; R-Smads, receptor-regulated Smads; C-Smads, common-partner Smads