SIRT3 promotes metabolic maturation of human iPSC-derived cardiomyocytes via OPA1-controlled mitochondrial dynamics

作者全名："Wang, Rui; Xu, Hao; Tan, Bin; Yi, Qin; Sun, Yanting; Xiang, Han; Chen, Tangtian; Liu, Huiwen; Xie, Qiumin; Wang, Li; Tian, Jie; Zhu, Jing"

作者地址："[Wang, Rui; Xu, Hao; Tan, Bin; Yi, Qin; Sun, Yanting; Xiang, Han; Chen, Tangtian; Liu, Huiwen; Xie, Qiumin; Wang, Li; Tian, Jie; Zhu, Jing] Chongqing Med Univ, Dept Pediat Res Inst, Natl Clin Res Ctr Child Hlth & Disorders, Minist Educ Key Lab Child Dev & Disorders,Children, Chongqing, Peoples R China; [Xu, Hao] Chongqing Med Univ, Dept Clin Lab, Childrens Hosp, Chongqing, Peoples R China; [Tian, Jie] Chongqing Med Univ, Dept Cardiovasc Internal Med, Childrens Hosp, Chongqing, Peoples R China; [Zhu, Jing] Chongqing Med Univ, China Int Sci & Technol Cooperat Base Child Dev &, Childrens Hosp, Box 136,3 Zhongshan RD, Chongqing 400014, Peoples R China"

通信作者："Zhu, J (通讯作者)，Chongqing Med Univ, China Int Sci & Technol Cooperat Base Child Dev &, Childrens Hosp, Box 136,3 Zhongshan RD, Chongqing 400014, Peoples R China."

来源：FREE RADICAL BIOLOGY AND MEDICINE

ESI学科分类：BIOLOGY & BIOCHEMISTRY

WOS号：WOS:000915582400001

JCR分区：Q1

影响因子：7.4

年份：2023

卷号：195

期号：　

开始页：270

结束页：282

文献类型：Article

关键词：Human iPSC-derived cardiomyocytes; SIRT3; Mitochondrial dynamics; Metabolism remodeling; OPA1

摘要："The metabolic patterns and energetics of human induced pluripotent stem cell-derived cardiomyocytes (HiPSCCMs) are much less than those of normal adult cardiomyocytes, which has limited their application in disease therapy and regenerative medicine. It has been demonstrated that SIRT3, a mitochondria-target deacetylase, controls mitochondrial metabolism in physiological and pathological conditions. In this research, We investigated the role and regulatory mechanism of SIRT3 in energy metabolism in HiPSC-CMs. We found that the expression of SIRT3 was increased during the differentiation and maturation of HiPSC-CMs. Knocking down SIRT3 impaired mitochondrial structure, mitochondrial respiration capacity, and fatty acid oxidation but enhanced glycolysis. However, honokiol, a pharmacological activator of SIRT3, improved the mitochondrial ultrastructure and energetics, and promoted oxidative phosphorylation in HiPSC-CMs. Furthermore, SIRT3 regulated the acetylation of OPA1, and the knockdown of OPA1 blocked the promotion of energy metabolism by honokiol, meanwhile, knocking down OPA1 impaired mitochondrial fusion, mitochondrial respiration capacity, and fatty acid oxidation which were reversed by M1 (a mitochondrial fusion promoter) in HiPSC-CMs. In summary, SIRT3 regulated energetics and promoted metabolism remodeling by targeting the OPA1-controlled mitochondrial dynamics in HiPSC-CMs, and targeting SIRT3 may have revelatory implications in the treatment of cardiovascular diseases and the application of HiPSC-CMs to regenerative medicine."

基金机构："National Natural Science Founda-tion of China [81700250, 81670270]"

基金资助正文：This study was supported by the National Natural Science Founda-tion of China (Grant Numbers 81700250 and 81670270) . We are grateful to all authors who participated in this research.