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.

项目总结/摘要 细胞器间通讯在维持细胞内环境稳定中起着重要作用 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， 细胞内稳态虽然众所周知，线粒体动力学经常被改变， 在动物衰老过程中，细胞器之间是否以及如何相互作用， 通讯在线粒体动力学的年龄依赖性改变中起着至关重要的作用。像 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，醚 磷脂生物合成）。然而，过氧化物酶体衰老研究是一个研究不足的领域。在这 我们将联合收割机CRISPR基因组编辑、细胞器蛋白质组学、代谢组学和 尖端的成像工具，以调查过氧化物酶体的重要作用， 动物衰老中的沟通这项提议是基于我们先前令人兴奋的发现， 过氧化物酶体受体蛋白Pex 5的激活不仅挽救了年龄依赖性衰老， 过氧化物酶体的进口，但也保存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的生物合成参与线粒体的调节， 动力学此外，我们发现了一种新的正反馈回路， 氧化应激下磷脂合成途径。 在本建议中，我们将解决两个悬而未决的问题：1）为什么和如何 过氧化物酶体输入随年龄下降？2)过氧化物酶体功能障碍是如何影响 老化？细胞器间的交流会是一种核心机制吗？拟议的工作将 提供了新的见解的重要作用，过氧化物酶体-酶通讯， 动物的健康衰老和长寿。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年龄下降。具体目标2。确定的作用 过氧化物酶体衍生的醚磷脂在年龄相关的线粒体动力学改变。 具体目标3。确定ATF 4在Gnpat和过氧化物酶体转录调控中的作用 老化过程中醚磷脂的生物合成。