TMPRSS6 cleaves KCNE1 and causes arrhythmias in iron overload disease

Iron storage disease is associated with cardiovascular manifestations, including various forms of cardiac arrhythmias of unknown origin. In this study, cardiac arrhythmias associated with iron overload were investigated in human iPSC-derived cardiomyocytes (hiPSC-CM) and hiPSC-derived sinus node-like pacemaker cells. Among other effects, iron overload leads to an increase in the plasma membrane-anchored protease TMPRSS6. TMPRSS6 cleaves the auxiliary subunit KCNE1 N-terminally and thus modulates the function of both the I _Ks (KCNQ1/KCNE1 current) and the I _f (HCN4/KCNE1) ion channels. Furthermore, TMPRSS6 induces a reduction of electric field potential (EFP) count and increased duration in hiPSC-derived ventricular-like cells and in hiPSC-derived pacemaker-like cells. In accordance with these in vitro generated results, TMPRSS6-mediated interactions show pro-arrhythmic effects in silico . Therefore, the TMPRSS6 - KCNE1-KCNQ1 and TMPRSS6 - KCNE1-HCN4 cascades may represent new clinically relevant pro-arrhythmic mechanisms in iron overload diseases.