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Defining intracellular mitochondrial heterogeneity establishment and maintenance

定义细胞内线粒体异质性的建立和维持

基本信息

批准号：
10436786
负责人：
Corey Nathaniel Cunningham
金额：
$ 6.76万
依托单位：
UNIVERSITY OF UTAH
依托单位国家：
美国
项目类别：
财政年份：
2021
资助国家：
美国
起止时间：
2021-07-01 至 2023-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10436786
关键词：
Address Affect Affinity Chromatography Amino Acids Anabolism Apoptosis Area Biochemical Biochemistry Biological Assay Biology Brown Fat Cell physiology Cells Cellular Stress Cellular biology Characteristics Clustered Regularly Interspaced Short Palindromic Repeats Communication Diabetes Mellitus Disease Distal Endoplasmic Reticulum Endosomes Equilibrium Event Functional disorder Goals Golgi Apparatus Heme Heterogeneity Homeostasis Human Individual Label Letters Lipids Lysosomes Maintenance Malignant Neoplasms Maps Measurement Mediating Membrane Metabolic Metabolism Microscopy Mitochondria Mitochondrial Proteins Modification Natural Immunity Normal Cell Organelles Oxidation-Reduction Oxidative Phosphorylation Physiological Physiology Play Population Post-Translational Modification Alteration Production Protein Precursors Proteins Proteome Proteomics Publishing Role Specificity TOM translocase Techniques Testing Triglycerides base comparative experimental study genetic manipulation heme biosynthesis innovation insight lipid biosynthesis metabolic profile metabolomics non-alcoholic fatty liver disease peroxisome quantitative imaging respiratory tool

项目摘要

Project Summary Mitochondria are the subcellular compartment responsible for a majority of cellular metabolic events including oxidative phosphorylation, heme biosynthesis, and other metabolic fluxes. Given the common depictions of mitochondrial physiology, it is striking that two recent studies have discovered subsets of mitochondria that are specialized in their functions and composition (2,10). In accordance with these findings, we posit the innovative hypothesis that intracellular mitochondrial heterogeneity exists in cells and is maintained through intracellular organelle-communication. In this proposal, we will define intracellular mitochondrial heterogeneity and discover the characteristics of specialized mitochondria. Using independent techniques: 1) CRISPR-mediated endo- tagging of select mitochondrial protein; 2) Proximity labeling and affinity purification of mitochondria, isolated mitochondrial populations will undergo comparative proteomics and metabolomics with Steven Gygi (see attached letter). A potential mechanism to establish mitochondrial heterogeneity in cells is to have distinct modes of intracellular communication. In this context, we propose that organelle proximity (ER, Golgi, peroxisome, lysosome, endosome, and lipid droplets) is necessary for the establishment and maintenance of specialized mitochondria by changing their individual proteomes and thus, mitochondrial function and metabolism. Additionally, we aim to uncover the roles for intracellular mitochondrial heterogeneity in cellular homeostasis. Overall, the insights gained from the proposed experiments will provide an innovative and exciting perspective on mitochondrial biology and homeostasis.

项目概要线粒体是负责大多数细胞代谢事件的亚细胞区室，包括氧化磷酸化、血红素生物合成和其他代谢通量。鉴于常见的描述线粒体生理学中，令人惊讶的是最近的两项研究发现了线粒体的子集专门研究它们的功能和组成 (2,10)。根据这些发现，我们提出了创新的细胞内线粒体异质性存在于细胞中并通过细胞内线粒体维持的假设细胞器通讯。在本提案中，我们将定义细胞内线粒体异质性并发现特化线粒体的特征。使用独立技术：1）CRISPR介导的内切标记选定的线粒体蛋白； 2) 线粒体的邻近标记和亲和纯化，分离线粒体群体将与 Steven Gygi 一起进行比较蛋白质组学和代谢组学（参见附信）。在细胞中建立线粒体异质性的一个潜在机制是具有不同的细胞内通讯的方式。在这种情况下，我们建议细胞器接近度（ER、高尔基体、过氧化物酶体、溶酶体、内体和脂滴）对于建立和维持是必需的通过改变个体蛋白质组来特化线粒体，从而改变线粒体功能和代谢。此外，我们的目标是揭示细胞内线粒体异质性在细胞中的作用体内平衡。总体而言，从拟议的实验中获得的见解将提供创新和关于线粒体生物学和稳态的令人兴奋的观点。