细胞器互作调控线粒体应激的分子机制及其生理病理功能

Mitochondrion is one of the most essential organelles in the cell. They not only provide energy to the cell, but also participate in numerous signaling pathways and programmed cell death. The proper function of mitochondria is often challenged by intrinsic stimuli such as reactive oxygen species, or by extrinsic pathogens and xenobiotics. Mitochondrial dysfunction has been implicated in aging and age-related diseases such as neurodegeneration, cardiovascular and metabolic diseases. The current study aims to understand the regulatory mechanisms of inter-organelle communications in mitochondrial stress response, and their implications in physiology and pathology. In our previous work, we performed a genome-wide screen and found that genes encoding nuclear transport factors or endosomal proteins are required for the induction of mitochondrial stress response. Later studies showed that mitochondrial-nuclear communication and mitochondrial-endosomal contact both play a role in mitochondrial stress response. In this proposal, we will focus on these two types of inter-organelle communications to further define the molecular mechanism of (1) mitochondrial-nuclear communication and (2) mitochondrial-endosomal contact in mediating mitochondrial stress response, and (3) the implications of these two types of inter-organelle communications in physiology and pathology. This study will broaden our knowledge of mitochondrial stress response and inter-organelle communication. It will also provide potential therapeutic targets for the treatment of mitochondrial disorders and age-related diseases.

线粒体是细胞内最重要的细胞器之一：它不但为细胞提供能量，同时也参与许多信号转导通路和细胞凋亡过程。线粒体经常受到来自于细胞内部的氧化压力或细胞外部的病原菌胁迫，其损伤是衰老相关疾病如神经退行性疾病、心血管和代谢疾病的重要诱因之一。本项目旨在研究细胞器互作对线粒体应激的调控机制及其生理病理功能。项目前期通过全基因组筛选发现，编码核膜蛋白和内体蛋白的基因对线粒体应激的正常启动至关重要。进一步研究显示线粒体应激时存在线粒体与核膜的信号交流传递，同时存在线粒体与内体的相互作用。本研究将以这两类细胞器互作为研究对象，重点阐明(1)线粒体与核膜的信号交流如何介导线粒体应激；（2）线粒体与内体互作参与线粒体应激的分子机制；（3）这两类细胞器互作对正常生理的贡献以及在线粒体疾病病理条件下的功能。以上研究将加深对线粒体应激和细胞器互作的理解，同时为线粒体疾病及衰老相关疾病的治疗提供靶向基因。

线粒体是细胞内最重要的细胞器之一：它不但为细胞提供能量，同时也参与许多信号转导通路和细胞凋亡过程。线粒体经常受到来自于细胞内部的氧化压力或细胞外部的病原菌胁迫，其损伤是衰老相关疾病如神经退行性疾病、心血管和代谢疾病的重要诱因之一。本项目关注于细胞器互作对线粒体应激的调控机制及其生理病理功能。发现了去SUMO化修饰蛋白ULP-4、组蛋白去乙酰化蛋白HDA-1和剪接因子PRP-19介导线粒体-细胞核的信号交流从而激活线粒体应激。此外，我们也发现亲代在遭遇线粒体胁迫后，可以通过线粒体-细胞核的信号交流将线粒体应激信号传递至后代，提高后代对胁迫环境的适应性。除此之外，我们也研究了细胞器对于营养物质感知和代谢调控的作用，发现了溶酶体依赖的氨基酸感知蛋白，并发现HLH-11/TFAP4通过溶酶体-蛋白酶体-细胞核的信号交流激活饥饿状态下的脂质水解。这些研究成果加深了我们对细胞器互作参与线粒体应激和营养物质感知的理解，同时为线粒体疾病及衰老相关疾病的治疗提供了靶向基因。