Role of peroxisome-mitochondrion communication in tissue aging

项目摘要/摘要 细胞器间的通讯在维持细胞内环境稳定方面起着至关重要的作用 和动物的衰老。线粒体作为一个高度动态的细胞器和细胞的代谢中枢， 经常与其他细胞器相互作用，以协调代谢过程并维持 细胞动态平衡。尽管众所周知，线粒体动力学经常会改变 在动物衰老过程中，细胞器间是否以及如何相互作用在很大程度上仍然没有答案。 在线粒体动力学随年龄变化的过程中，通讯起着至关重要的作用。喜欢 线粒体、过氧酶体在氧化还原和脂类代谢(如乙醚)中起着重要作用 磷脂生物合成)。然而，对过氧化物体衰老的研究还不够深入。在这 我们将结合CRISPR基因组编辑、细胞器蛋白质组学、代谢组学和 研究过氧化体-线粒体重要作用的尖端成像工具 动物衰老中的沟通。这项建议是基于我们之前令人兴奋的发现 Peroxisomal受体蛋白Pex5的激活不仅挽救了年龄依赖性的衰老 过氧化体的导入，还保存了线粒体的结构和功能。我们进一步表明， 过氧化物醚磷脂的生物合成参与线粒体的调节 动力学。此外，我们还发现了一种新的正反馈回路，它调节以太 氧化应激下的磷脂合成途径。 在这项提案中，我们将解决两个悬而未决的问题：1)为什么以及如何 随着年龄的增长，过氧化物体进口下降？2)过氧化物体功能障碍如何影响细胞 变老？细胞器间的沟通可能是一种核心机制吗？拟议的工作将 为过氧化物酶体-线粒体通讯的重要作用提供了新的见解 动物健康、衰老和长寿。提出了三个具体目标：具体目标1.确定 过氧化体导入功能如何随着年龄的增长而下降。具体目标2.确定 过氧化物酶体衍生的乙醚磷脂与年龄相关的线粒体动力学改变。 特定目的3.确定ATF4在Gnpat和过氧化物体转录调控中的作用 老化过程中乙醚磷脂的生物合成。

Project Summary/Abstract Inter-organelle communication plays an essential role in maintaining cellular homeostasis and animal aging. Mitochondria, as a highly dynamic organelle and the metabolic hub of the cell, frequently interact with other cellular organelles to coordinate metabolic processes and maintain cellular homeostasis. Although it is well known that mitochondrial dynamics are often altered during animal aging, it remains largely unanswered whether and how inter-organelle communication plays a crucial role in age-dependent alternations of mitochondrial dynamics. Like mitochondria, peroxisomes play an important role in redox and lipid metabolism (e.g., ether phospholipid biosynthesis). However, peroxisome aging research is an understudied area. In this proposal, we will combine CRISPR genome editing, organelle proteomics, metabolomics, and cutting-edge imaging tools to investigate the important role of peroxisome-mitochondrion communication in animal aging. The proposal is based on our previous exciting findings showing that activation of peroxisomal receptor protein Pex5 not only rescued age-dependent decline of peroxisomal import, but also preserved mitochondrial structure and function. We further show that peroxisomal ether phospholipid biosynthesis is involved in the regulation of mitochondrial dynamics. Furthermore, we uncovered a novel positive feedback loop that regulates the ether phospholipid synthesis pathway under oxidative stress. In this proposal, we will address two outstanding questions: 1) Why and how does peroxisomal import decline with age? 2) How does peroxisomal dysfunction contribute to cellular aging? Could inter-organelle communication be a core mechanism? The proposed work will provide novel insights into the significant role of peroxisome-mitochondrion communication in animal health aging and longevity. Three specific aims are proposed: Specific Aim 1. Determine how peroxisomal import function declines with age. Specific Aim 2. Determine the role of peroxisome-derived ether phospholipids in age-related alterations of mitochondrial dynamics. Specific Aim 3. Determine the role of ATF4 in transcriptional regulation of Gnpat and peroxisomal ether phospholipid biosynthesis during aging.