Lamin A/C deficiency-mediated ROS elevation contributes to pathogenic phenotypes of dilated cardiomyopathy in iPSC model
Hangyuan Qiu, Yaxun Sun, Xiaochen Wang, Tingyu Gong, Jun Su, Jiaxi Shen, Jingjun Zhou, Jiafeng Xia, Hao Wang, Xiangfu Meng, Guosheng Fu, Dong H. Zhang, Chenyang Jiang, Ping Liang
Abstract
Mutations in the nuclear envelope (NE) protein lamin A/C (encoded by LMNA), cause a severe form of dilated cardiomyopathy (DCM) with early-onset life-threatening arrhythmias. However, molecular mechanisms underlying increased arrhythmogenesis in LMNA-related DCM (LMNA-DCM) remain largely unknown. Here we show that a frameshift mutation in LMNA causes abnormal Ca2+ handling, arrhythmias and disformed NE in LMNA-DCM patient-specific iPSC-derived cardiomyocytes (iPSC-CMs). Mechanistically, lamin A interacts with sirtuin 1 (SIRT1) where mutant lamin A/C accelerates degradation of SIRT1, leading to mitochondrial dysfunction and oxidative stress. Elevated reactive oxygen species (ROS) then activates the Ca2+/calmodulin-dependent protein kinase II (CaMKII)-ryanodine receptor 2 (RYR2) pathway and aggravates the accumulation of SUN1 in mutant iPSC-CMs, contributing to arrhythmias and NE deformation, respectively. Taken together, the lamin A/C deficiency-mediated ROS disorder is revealed as central to LMNA-DCM development. Manipulation of impaired SIRT1 activity and excessive oxidative stress is a potential future therapeutic strategy for LMNA-DCM. LMNA-related dilated cardiomyopathy (DCM) is an inherited cardiomyopathy featured by early-onset lethal arrhythmias, but the underlying mechanisms remain unclear. Here, the authors show that manipulation of impaired SIRT1 activity and excessive oxidative stress may offer new therapeutic strategies for LMNA-related DCM.