SIRT1 Ameliorates Lamin A/C Deficiency-Induced Cardiac Dysfunction by Promoting Mitochondrial Bioenergetics

Zunhui Du; Yanting Zhou; Qiheng Li; Yuan Xie; Tingfang Zhu; Jing Qiao; Ruihong Zhang; Yangyang Bao; Lingjie Wang; Yinyin Xie; Jinwei Quan; Menglu Lin; Ning Zhang; Qi Jin; Wenbin Liang; Liqun Wu; Tong Yin; Yucai Xie

doi:10.1016/j.jacbts.2024.05.011

SIRT1 Ameliorates Lamin A/C Deficiency-Induced Cardiac Dysfunction by Promoting Mitochondrial Bioenergetics

JACC Basic Transl Sci. 2024 Jul 31;9(10):1211-1230. doi: 10.1016/j.jacbts.2024.05.011. eCollection 2024 Oct.

Authors

Zunhui Du¹, Yanting Zhou², Qiheng Li¹, Yuan Xie³, Tingfang Zhu¹, Jing Qiao², Ruihong Zhang², Yangyang Bao¹, Lingjie Wang¹, Yinyin Xie², Jinwei Quan¹, Menglu Lin¹, Ning Zhang¹, Qi Jin¹, Wenbin Liang⁴, Liqun Wu¹, Tong Yin², Yucai Xie¹

Affiliations

¹ Department of Cardiovascular Medicine, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China.
² Shanghai Institute of Hematology, State Key Laboratory of Medical Genomics, National Research Center for Translational Medicine at Shanghai, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China.
³ College of Osteopathic Medicine, Kansas City University, Kansas City, Missouri, USA.
⁴ University of Ottawa Heart Institute, Department of Cellular and Molecular Medicine, University of Ottawa, Ottawa, Ontario, Canada.

Abstract

Dilated cardiomyopathy (DCM) is associated with high mortality despite advanced therapies. The LMNA gene encodes lamin A/C and is the second most frequently mutated gene associated with DCM, for which therapeutic options are limited. Here we generated Lmna ^-/- mice and found they exhibited cardiac dysfunction at the age of 1 month but not at 2 weeks. Proteomics showed down-regulation of mitochondrial function-related pathways in Lmna ^-/- hearts. Moreover, early injured mitochondria with decreased cristae density and sirtuin 1 (SIRT1) down-regulation were observed in 2-week-old Lmna ^-/- hearts. Adenoviral overexpression of SIRT1 in lamin A/C knockdown neonatal rat ventricular myocytes improved mitochondrial oxidative respiration capacity. Adeno-associated virus-mediated SIRT1 overexpression alleviated mitochondrial injury, cardiac systolic dysfunction, ventricular dilation, and fibrosis, and prolonged lifespan in Lmna ^-/- mice. Mechanistically, LMNA maintains mitochondrial bioenergetics through the SIRT1-PARKIN axis. Our results suggest that targeting the SIRT1 signaling pathway is expected to be a novel therapeutic strategy for LMNA mutation-associated DCM.

Keywords: LMNA; SIRT1; dilated cardiomyopathy; mitochondrial bioenergetics; proteomics.