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, Donghui Zhang, Chenyang Jiang () and Ping Liang ()
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Hangyuan Qiu: Zhejiang University School of Medicine
Yaxun Sun: Zhejiang University School of Medicine
Xiaochen Wang: Zhejiang University School of Medicine
Tingyu Gong: Zhejiang University School of Medicine
Jun Su: Zhejiang University School of Medicine
Jiaxi Shen: Zhejiang University School of Medicine
Jingjun Zhou: Zhejiang University School of Medicine
Jiafeng Xia: Zhejiang University School of Medicine
Hao Wang: Hangzhou Women’s Hospital
Xiangfu Meng: Hubei University
Guosheng Fu: Zhejiang University School of Medicine
Donghui Zhang: Hubei University
Chenyang Jiang: Zhejiang University School of Medicine
Ping Liang: Zhejiang University School of Medicine

Nature Communications, 2024, vol. 15, issue 1, 1-16

Abstract: 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.

Date: 2024
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DOI: 10.1038/s41467-024-51318-5

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