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
• 来源期刊: 中国药理学报（英文版）
• 年，卷（期）: 2021,（11）
• 所属期刊栏目: Cardiovascular Pharmacology
• 页码范围: 1790-1797
• 页数: 8页
• 语种: 英文

摘要

Rictor is a key component of the mammalian target of rapamycin complex 2 (mTORC2) and is required for Akt phosphorylation(Set473).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.