组蛋白去乙酰化酶 1 调控线粒体未折叠蛋白反应的分子机制及对衰老相关疾病的应用

Mitochondrial function is challenged by toxic products of metabolism as well as by pathogen attack. In respond to mitochondrial stress, animals activate mitochondrial unfolded protein response (UPRmt) to alleviate the stress and ensure mitochondrial homeostasis. UPRmt consisting of a signaling cascade upregulating an array of protective genes on detoxification, pathogen-response and mitochondrial -repair pathways. To better understand the UPRmt, we use C.elegans as a model organism to study mechanism. From a genome -wide RNA interference (RNAi) screen, our laboratory identified histone deacetylase 1 is required for UPRmt activation. Histone deacetylases' predominant function is regulating gene transcription by modifying histones and chromatin structure, while it also control the proteins' function, activity, and stability by post-translational modifications. Therefore, the current studies aim to understand the molecular mechanisms of histone deacetylase 1 in UPRmt. Besides, mitochondria play essential roles in aging and lifespan. Mild mitochondrial stress can have beneficial effects on the lifespan of organisms. Activating UPRmt via histone deacetylases mechanism may hold great promise for the therapeutics of age -related diseases such as neurodegeneration and extending lifespan..The applicant has received extensive trainings in genetics and biochemistry. During the past five years, the applicant has published several papers on Cell, Nature Cell Biology and eLife. The first-author research about non-autonomous UPRmt was published on the cover of Cell Research.

线粒体不仅对细胞功能非常重要，对机体的许多生理表型也有影响，例如衰老和寿命。细胞中负责监察与保护线粒体的是线粒体未折叠蛋白反应，然而，该反应被揭示的分子机制比较有限。本课题组通过RNAi线虫全基因组的方式，筛选到组蛋白去乙酰化酶1是活化线粒体未折叠蛋白反应所必需的。敲低组蛋白去乙酰化酶1会抑制线粒体压力刺激诱导的线粒体未折叠蛋白反应。此外，申请人在前期实验中发现，线虫中过表达组蛋白去乙酰化酶1能够一定程度上延缓衰老疾病。已知组蛋白去乙酰化酶能够修饰组蛋白和染色质结构以调控基因转录，也能够翻译后修饰调控蛋白的功能、活性和稳定性。申请人将利用生物化学、遗传学、生物信息学等方法，深入探究并阐明组蛋白去乙酰化酶1调控线粒体未折叠蛋白反应的新机制，为以后该方向的研究奠定基础。此外，申请人将应用该新机制于线虫衰老相关疾病的模型中，试图探寻延缓衰老相关疾病、延长健康寿命的有效方法。

线粒体未折叠蛋白反应（UPRmt）是监测并维持线粒体内稳态的重要机制。当感知到线粒体损伤时，UPRmt 会启动线粒体至细胞核的信号传导，转录出大量线粒体应激相关基因和代谢重编程基因。我们首次发现线虫组蛋白去乙酰化酶 HDA-1 是活化 UPRmt、诱导天然免疫反应和延长健康寿命所必需的，并且发现 HDA-1 影响线虫的衰老进程和衰老相关疾病。在分子机制上，HDA-1 结合并协同基因组的组织者 DVE-1 诱导转录大批 UPRmt 基因、天然免疫反应基因和代谢基因。此外，我们发现哺乳动物中 HDA-1 的同源蛋白 HDAC1/2 与 DVE-1 的同源蛋白 SATB2 也协同调控线粒体内稳态。在恒河猴和人的各种组织中，HDAC1/2 的转录水平与 UPRmt 相关基因的转录水平显著正相关。在哺乳动物细胞中，敲降 HDAC1/2 会抑制 UPRmt 的活化并破坏线粒体的正常管网化结构。综上，我们揭示了进化上保守的组蛋白去乙酰化酶 HDAC1/2 调控线粒体内稳态的机制，并且发现该机制影响机体的天然免疫能力、衰老和长寿。