热应激下HSF1-SSBP1复合体调节线粒体应激功能及机制的研究

Mitochondria supply the energy to cells and its function determines the cell fate. Our previous study proved that HSF1 and SSBP1 formed complex during heat shock , and provoked mitochondrial stress response through inducing mitochondrial heat shock proteins. In the further study, combing with DNA microarray analysis and confirmed real-time PCR results, we found that heat stress induced NRF1 expression dependent on HSF1-SSBP1 complex. NRF1 is an important transcription factor for mitochondrial biogenesis and function. However, how HSF1-SSBP1 complex regulates NRF1 expression and whether HSF1-SSBP1 complex regulates the mitochondrial function through NRF1 during heat shock is unknown. Here, we will use HSF1, SSBP1 , NRF1 knock-down cells, HSF1 over-expression cells and HSF1 wild-type, HSF1-KO mice to illuminate the induction of NRF1 and other mitochondrial-related genes during heat shock, explore the transcription mechanisms by which NRF1 is regulated by HSF1-SSBP1 complex, and show the effects of HSF1-SSBP1 complex on mitochondrial stress response, mitochondrial function and cell survival. The aim of this study is to discover the essential role of HSF1-SSBP1 complex in mitochondrial energy metabolism, uncover the new pathway and mechanism of mitochondrial stress response regulated by HSF1-SSBP1 complex, and provide theoretical basis for new approaches of mitochondrial-related diseases in the further.

线粒体为细胞提供能量，其功能的调节决定细胞生死。我们前期研究表明，热应激下HSF1和SSBP1形成复合体，通过诱导线粒体热休克蛋白而增强线粒体应激功能。后续研究中，通过基因芯片和定量检测发现，热应激时HSF1-SSBP1可以调节NRF1的表达。NRF1是维持线粒体生物合成和功能的关键因子。但热应激时HSF1-SSBP1调控NRF1的分子机制及是否通过NRF1来调控线粒体应激功能尚无报道。本项目以HSF1、SSBP1 、NRF1低表达与HSF1过表达细胞和小鼠（WT、HSF1-KO）为材料，通过研究HSF1-SSBP1对NRF1等线粒体关键基因的诱导作用及分子调控机制，进一步探讨HSF1-SSBP1通过诱导NRF1调节线粒体应激功能和细胞生存的途径，阐明HSF1-SSBP1在线粒体能量代谢中的重要作用，揭示HSF1-SSBP1调控线粒体应激防御反应新的通路，为线粒体相关疾病治疗提供理论基础。

线粒体是一种必不可少的细胞器，具有多种生理功能，如ATP的生成、活性氧的产生、代谢活动和细胞死亡的调节等。NRF1是细胞内一种重要的线粒体转录因子，主要通过调节TFAM和线粒体相关基因的表达而促进线粒体的生物合成和功能。我们发现，热应激显著诱导NRF1 的mRNA和蛋白表达的上调。热应激条件下，HSF1-SSBP1作为转录因子复合物，通过与NRF1启动子结合，促进RNA转录酶II和染色质重组化合物等转录激活因子在NRF1启动子上的募集，直接介导NRF1的表达。降低HSF1或NRF1的表达显著抑制TFAM和线粒体相关基因的表达，同时伴随ROS产生增加、线粒体膜电位降低和细胞死亡加剧。因此，HSF1-SSBP1复合体在热应激条件下可通过NRF1-TFAM基因轴维持线粒体功能。这些结果揭示了热应激下细胞核与线粒体之间新的沟通通路，为线粒体相关疾病和癌症的治疗提供了新的理论基础和潜在治疗靶点。

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