内质网-线粒体互作对未折叠蛋白响应的调节及其生理意义

The Endoplasmic Reticulum (ER) and Mitochondrion (Mito) are two major eukaryotic organelles, which play important roles in protein folding and energy conversion. It remains a tempting question the mechanism and function of the physical contact and material exchange between ER and Mito. Protein misfolding and aggregation in the ER lumen triggers the Unfolded Protein Response (UPR), which relays to downstream pathways that help to maintain the protein homeostasis; however, UPR can also activate pro-apoptotic pathways through Mito. Recent studies found that malfunction in Mito could also lead to UPR, indicating that the activation of the UPR is regulated by both ER and Mito. We propose to understand the regulatory mechanism of ER-Mito interplay on the UPR, and to unravel the physiological significance of such inter-organelle interaction and how it relates to human diseases..ER-Mito contact sites are characterized by locally high Ca2+ concentration, the specialized membrane lipid components, and the flow of Ca2+ and exchange of lipids between the two organelles. Our preliminary data show that the UPR can be activated by upheaving cytosolic [Ca2+] or high concentration of ambient long saturated fatty acid such as palmitate, where the most conserved UPR pathway—IRE1alpha—is activated. The underlying mechanism remains elusive. In this proposal, we aim to explore the regulatory role of ER-Mito interplay on the UPR, especially via modulating the Ca2+ signal and the lipids components at the ER-Mito contact interface. We anticipate to understand the molecular mechanism of such regulation and its physiological significance, and to broaden our study on the UPR to inter-organelle level.

内质网（ER）和线粒体（Mito）是真核细胞蛋白质折叠和能量代谢的重要场所，两者间物理上的偶联和物质交换长期受关注。当ER内蛋白错误折叠和聚集时会启动“未折叠蛋白响应（UPR）”，触发一系列信号通路以维持蛋白质内稳态，也可通过影响Mito启动细胞凋亡。最近研究发现Mito功能异常也能引起UPR，说明UPR发生受ER和Mito共同影响。本项目关注ER-Mito互作对UPR的调控，并试图解释该调控的生理意义和与疾病的关系。.ER-Mito结合区有局部高钙环境，存在钙从ER向Mito的流动，也有特殊膜脂成分和两者间脂交换。我们前期工作发现，细胞质内高钙及长链饱和脂肪酸能引起UPR，激活UPR最保守通路—IRE1alpha，但相关机制未知。我们拟探索ER和Mito互作是否通过ER-Mito结合区钙流动及脂成分变化调控IRE1alpha，揭示其分子机制和生理意义，将UPR研究拓展到跨细胞器领域。