Rictor/mTORC2 involves mitochondrial function in ES cells derived cardiomyocytes via mitochondrial Connexin 43  

作　　者：Jia-dan Wang Ying Shao Dan Liu Nuo-ya Liu Dan-yan Zhu 

机构地区：[1]Institute of Pharmacology and Toxicology,Zhejiang University,Hangzhou 310058,China [2]Xiaoshan Traditional Chinese Medical Hospital,Hangzhou 311201,China

出　　处：《Acta Pharmacologica Sinica》2021年第11期1790-1797,共8页中国药理学报（英文版）

基　　金：supported by National Key R&D Program of China(No.2017YFE0102200);the National Natural Science Foundation of China(No.81573426);the State Key Program of National Natural Science Foundation of China(No.81730101);Public Welfare Project of Zhejiang Provincial Science and Technology Department(No.LGF21H310005).

摘　　要：Rictor is a key component of the mammalian target of rapamycin complex 2(mTORC2)and is required for Akt phosphorylation(Ser473).Our previous study shows that knockdown of Rictor prevents cardiomyocyte differentiation from mouse embryonic stem(ES)cells and induces abnormal electrophysiology of ES cell-derived cardiomyocytes(ESC-CMs).Besides,knockdown of Rictor causes down-expression of connexin 43(Cx43),the predominant gap junction protein,that is located in both the sarcolemma and mitochondria in cardiomyocytes.Mitochondrial Cx43(mtCx43)plays a crucial role in mitochondrial function.In this study,we used the model of cardiomyocyte differentiation from mouse ES cells to elucidate the mechanisms for the mitochondrial damage in ESC-CMs after knockdown of Rictor.We showed swollen and ruptured mitochondria were observed after knockdown of Rictor under transmission electron microscope.ATP production and mitochondrial transmembrane potential were significantly decreased in Rictor-knockdown cells.Furthermore,knockdown of Rictor inhibited the activities of mitochondrial respiratory chain complex.The above-mentioned changes were linked to inhibiting the translocation of Cx43 into mitochondria by knockdown of Rictor.We revealed that knockdown of Rictor inactivated the mTOR/Akt signalling pathway and subsequently decreased HDAC6 expression,resulted in Hsp90 hyper-acetylation caused by HDAC6 inhibition,thus,inhibited the formation of Hsp90-Cx43-TOM20 complex.In conclusion,the mitochondrial Cx43 participates in shRNA-Rictor-induced mitochondrial function damage in the ESC-CMs.

关 键 词：Rictor/mTORC2 embryonic stem cell MITOCHONDRIA CONNEXIN43 cardiomyocyte differentiation 

分 类 号：R96[医药卫生—药理学]