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Regulation of RNA processing on the mitochondrial surface by lipid signaling

通过脂质信号传导调节线粒体表面的 RNA 加工

基本信息

批准号：
9016170
负责人：
Michael A. Frohman
金额：
$ 5.32万
依托单位：
STATE UNIVERSITY NEW YORK STONY BROOK
依托单位国家：
美国
项目类别：
财政年份：
2012
资助国家：
美国
起止时间：
2012-09-01 至 2016-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9016170
关键词：
1,2-diacylglycerol Adaptor Signaling Protein Affect Animal Model Area Binding Binding Proteins Biochemical Biogenesis Biological Biological Process Brain Bypass C-terminal Cardiac Cell Line Cell membrane Cells Centrosome Charge Complex Cytoplasmic Granules Diacylglycerol Kinase Diglycerides Electrons Electrostatics Endoplasmic Reticulum Enzymes Epigenetic Process Event Failure Gene Structure Generations Genes Genomics Germ Lines Health Hereditary Disease Kinesin Link Lipids Male Contraceptive Agents Male Infertility Malignant Neoplasms Mediator of activation protein Meiosis Mesenchymal Stem Cells Methylation Microtubules Mitochondria Mitochondrial RNA Motor Movement Nature Nuclear Organelles Pathway interactions Phenotype Phosphatidate Phosphatase Phosphatidic Acid Play Process Production Proteins RNA RNA Interference RNA Processing Regulation Reporting Research Role Signal Transduction Small RNA Source Spermatocytes Spermatogenesis Structure Surface Therapeutic Tissues Transcript Transmembrane Domain Work base cancer type extracellular genome integrity imprint member novel piRNA research study response sensor tool development trafficking

项目摘要

DESCRIPTION (provided by applicant): Mitochondria, once viewed as the "simple" powerhouse of the cell, are increasingly recognized to be involved in many different cell biological processes that involve interaction with non-mitochondrial organelles such as the endoplasmic reticulum and plasma membrane. These interactions take place in part via machinery on the mitochondrial surface that generates and senses protein and lipid signals, which has been an area of focus for us in the context of mitochondrial dynamics (fusion) and changes in energetic in response to extracellular signaling events. Our recent work has uncovered a new role for mitochondria in a specialized form of RNA processing that appears to take place at the interface between the mitochondrial surface and juxtaposed RNA granules. More specifically, we have linked a signaling enzyme on the mitochondrial surface to the production of piRNAs, a third type of RNAi, in an electron-dense structure known as nuage that is similar to P-bodies. Using cell biological, in culture, and animal model approaches, we propose to study how lipid signaling at the mitochondrial surface promotes this newly identified physical and functional interaction between mitochondria and RNA-processing complexes via underlying mechanisms that potentially include kinesin-regulated trafficking of RNAs, processing granules and mitochondria on microtubules. Relevance: This initial story applies to a pathway that is critical for spermatogenesis, has relevance to male infertility, and offers opportunities fr a novel type of male contraceptive. However, other types of RNA recruitment to and processing at the mitochondrial surface are known and represent a broader context in which this newly identified pathway will likely be important, including in connection to mesenchymal stem cells, brain and cardiac function, and cancer.

描述（由申请人提供）：线粒体，曾经被认为是细胞的“简单”动力，越来越多的人认识到它参与了许多不同的细胞生物学过程，包括与非线粒体细胞器（如内质网和质膜）的相互作用。这些相互作用部分是通过线粒体表面产生和感知蛋白质和脂质信号的机制发生的，这是我们在线粒体动力学（融合）和响应细胞外信号事件的能量变化的背景下关注的一个领域。我们最近的工作揭示了线粒体在一种特殊形式的RNA加工中的新作用，这种RNA加工似乎发生在线粒体表面和并立RNA颗粒之间的界面上。更具体地说，我们已经将线粒体表面的一种信号酶与pirna的产生联系起来，pirna是第三种类型的RNAi，其电子密度结构被称为nuage，与p体相似。利用细胞生物学、培养和动物模型方法，我们建议研究线粒体表面的脂质信号如何通过潜在的机制促进线粒体和rna加工复合物之间新发现的物理和功能相互作用，这些机制可能包括驱动蛋白调节的rna运输、加工颗粒和微管上的线粒体。相关性：这个最初的故事适用于对精子发生至关重要的途径，与男性不育有关，并为新型男性避孕药提供了机会。然而，其他类型的RNA在线粒体表面的募集和加工是已知的，并且代表了一个更广泛的背景，在这个新发现的途径可能很重要，包括与间充质干细胞、脑和心脏功能以及癌症有关。