Role of peroxisome-mitochondrion communication in tissue aging

过氧化物酶体-线粒体通讯在组织衰老中的作用

• 批准号: 10736217
• 负责人: Hua Bai
• 金额: $ 30.22万
• 依托单位: IOWA STATE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-08-01 至 2028-04-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10736217
• 关键词: Age; Aging; Anabolism; Animals; Area; Attenuated; Binding; Binding Proteins; Biological Assay; Cell Aging; Cells; Clustered Regularly Interspaced Short Palindromic Repeats; Communication; Disease; Drosophila genus; Enzymes; Feedback; Functional disorder; Genetic Transcription; Goals; Health; Hepatocyte; Homeostasis; Imaging Device; Impairment; Intervention; Lipids; Longevity; Mediating; Metabolic; Metabolism; Mitochondria; Monoubiquitination; Morphology; Organelles; Oxidation-Reduction; Oxidative Stress; PXR1 protein; Pathology; Pathway interactions; Phospholipid Ethers; Phosphorylation; Phosphotransferases; Plasmalogens; Play; Protein Import; Proteins; Proteomics; Reactive Oxygen Species; Recycling; Regulation; Research; Role; Site; Stress; Structure; Testing; Tissues; Transcriptional Regulation; Up-Regulation; Very Long Chain Fatty Acid; Work; age related; biological adaptation to stress; fusion gene; genetic manipulation; genome editing; human old age (65+); insight; interdisciplinary approach; lipid metabolism; metabolomics; novel; overexpression; oxidation; peroxisome; preservation; receptor; recruit; repaired; ubiquitin ligase

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.

项目概要/摘要 细胞器间通讯在维持细胞稳态中发挥着重要作用 和动物衰老。线粒体作为一种高度动态的细胞器和细胞的代谢中心， 经常与其他细胞器相互作用以协调代谢过程并维持 细胞稳态。尽管众所周知线粒体动力学经常发生改变 在动物衰老过程中，细胞器间是否以及如何相互作用仍然很大程度上没有得到解答 通讯在线粒体动力学的年龄依赖性变化中发挥着至关重要的作用。喜欢 线粒体、过氧化物酶体在氧化还原和脂质代谢（例如乙醚 磷脂生物合成）。然而，过氧化物酶体衰老研究是一个尚未得到充分研究的领域。在这个 提案中，我们将结合 CRISPR 基因组编辑、细胞器蛋白质组学、代谢组学和 使用尖端成像工具研究过氧化物酶体线粒体的重要作用 动物衰老过程中的沟通。该提案基于我们之前令人兴奋的发现 过氧化物酶体受体蛋白 Pex5 的激活不仅可以挽救年龄依赖性的衰退 过氧化物酶体的导入，还保留了线粒体的结构和功能。我们进一步表明 过氧化物酶体醚磷脂生物合成参与线粒体的调节 动力学。此外，我们发现了一种新颖的正反馈循环来调节以太 氧化应激下的磷脂合成途径。 在本提案中，我们将解决两个悬而未决的问题：1）为什么以及如何 过氧化物酶体输入随着年龄的增长而下降？ 2) 过氧化物酶体功能障碍如何影响细胞 老化？细胞器间通讯可能是核心机制吗？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 过氧化物酶体输入功能如何随着年龄的增长而下降。具体目标 2. 确定角色 过氧化物酶体衍生的醚磷脂在与年龄相关的线粒体动力学改变中的作用。 具体目标 3. 确定 ATF4 在 Gnpat 和过氧化物酶体转录调控中的作用 衰老过程中醚磷脂的生物合成。