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.

项目摘要/摘要 轨道间的交流在维持细胞稳态中起着至关重要的作用 和动物衰老。线粒体作为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，线粒体动力通常会改变 在动物衰老期间，它在很大程度上尚未得到答复 在线粒体动力学的年龄依赖性交替中，沟通起着至关重要的作用。喜欢 线粒体，过氧化物酶体在氧化还原和脂质代谢中起重要作用（例如 磷脂生物合成）。但是，过氧化物酶体衰老研究是一个研究的领域。在这个 提案，我们将结合CRISPR基因组编辑，Organelle蛋白质组学，代谢组学和 尖端的成像工具，以研究过氧化物酶体单聚体的重要作用 动物老化的交流。该提案基于我们以前令人兴奋的发现 过氧化物酶体受体蛋白PEX5的激活不仅挽救了年龄依赖的下降 过氧化物酶体导入，但也保留了线粒体的结构和功能。我们进一步表明 过氧化物酶体磷脂生物合成与线粒体的调节有关 动力学。此外，我们发现了一个新颖的积极反馈循环，以调节以太 氧化应激下的磷脂合成途径。 在此提案中，我们将解决两个出色的问题：1）为什么以及如何 过氧化物酶体的进口下降随着年龄的增长吗？ 2）过氧化物酶体功能障碍如何有助于细胞 老化？轨道间的交流可以成为核心机制吗？拟议的工作将 提供新的见解，以了解过氧化物酶体单位体通信在 动物健康衰老和寿命。提出了三个具体目标：具体目标1。 过氧化物酶体进口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。 具体目标3。确定ATF4在GNPAT和过氧化物酶体的转录调节中的作用 衰老过程中的乙醚磷脂生物合成。