YAP对细胞线粒体功能的影响及其生物学意义研究

Effects of YAP in the Regulation of Mitochondrial Function

YAP(yes-associated protein)是Hippo信号通路中发挥转录共激活作用的蛋白。已知YAP能够参与细胞的多个代谢过程,但YAP是否参与了线粒体功能的调控尚不清楚。该研究发现,无论是化合物抑制YAP功能还是基因敲低YAP表达水平均能够显著提升线粒体呼吸链组装水平,并促进线粒体呼吸能力的上升和膜电位的升高。初步的机制分析表明,YAP基因功能的抑制可正向调控促进线粒体生物能学的相关转录因子Nrf1、RXRα和POLG的表达;负向调控抑制线粒体生物能学的转录因子HIF1-alpha的表达。进一步的生物学功能分析表明,葡萄糖应激或者葡萄糖剥夺下线粒体功能的上升部分依赖于YAP表达量的抑制。综上,该研究发现,YAP可通过调节线粒体功能调控相关转录因子的表达来影响线粒体功能,且葡萄糖应激条件下线粒体功能的维持可通过YAP途径实现。

YAP (yes-associated protein) is transcriptional co-activator and functions as a downstream effector of Hippo signaling pathway.YAP has been recognized as a transcriptional regulator of multiple metabolic enzymes,however its role in the regulation of mitochondrial function is not known.In this study,inhibition of YAP by either chemical or KD (gene knockdown) in HeLa cells enhanced mitochondrial function by increase the assembly of mitochondrial respiratory chain complexes.Mechanistically,KD of YAP positively regulates the expression of transcriptional factors related to mitochondrial biogenesis including Nrf1,RXRα,and POLG.Whereas HIF1-alpha,a transcriptional factor which negatively associated with mitochondrial function,was inhibited by the KD of YAP in HeLa cells.Moreover,decreased expression of YAP may be responsible for the enhanced mitochondrial function in glucose deprived HeLa cells.Altogether,YAP is a negative regulator of mitochondrial function and its suppression in glucose deprived cells enhances mitochondrial function.