Wnt信号通路调控线粒体应激反应的分子机制研究

线粒体未折叠蛋白反应（UPRmt）是重要的线粒体质量监控通路，也是线粒体损伤状态下的一种应激反应。UPRmt的激活使分子伴侣、蛋白酶等表达水平上调，修复线粒体蛋白质稳态平衡，并调节代谢相关基因表达和激活免疫通路，因此对于维持细胞的正常生理功能非常重要。调控UPRmt的分子机制在线虫中已经有了部分基础，但是关于UPRmt在哺乳动物中的调控机制以及参与的生理过程，还没有太多的报道。申请人前期的研究发现Wnt/β-catenin这一条高度保守的信号通路参与UPRmt调控，并且Wnt可以通过细胞非自主的方式调控其他组织的UPRmt。因此，本项目将全面展开研究Wnt蛋白在内质网内是如何感知线粒体应激和如何传递线粒体应激信号，以及如何通过下游Wnt/β-catenin激活UPRmt的分子机制。该项目的研究会扩展我们对于经典Wnt通路参与线粒体应激和代谢调控的全新认识，并有助于探索UPRmt的重要生理功能。

The mitochondrial unfolded protein response (UPRmt) is an important protein quality control pathway to relieve mitochondrial damage and respond to proteotoxic stress specifically in mitochondria. The activation of UPRmt induces a protective transcriptional response including an up-regulation of mitochondrial chaperones and proteases, metabolic adaptations, as well as an innate immunity program. Therefore, UPRmt is essential for maintaining the normal physiological functions of cells. More recent work in C. elegans has identified a number of components required for UPRmt activation. However, the molecular mechanism in mammals and the physiological processes involved in UPRmt regulation remain elusive. Our previous study showed that Wnt/β-catenin, a highly conserved signaling pathway, is involved in the UPRmt regulation. Wnt signaling also regulates UPRmt in a cell-non-autonomous manner. In this proposal, we will explore how Wnt proteins sense mitochondrial stress, transmit the mitochondrial stress signal to the peripheral tissues, and initiate the UPRmt program through Wnt/β-catenin signaling pathway. The results will extend our understanding of the canonical Wnt signaling in the UPRmt regulation and metabolic adaptations.