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：
8372464
负责人：
Michael A. Frohman
金额：
$ 29.85万
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/8372464
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 Genome 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 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. PUBLIC HEALTH RELEVANCE: Mobilization of transposons can cause genetic diseases including cancer. piRNAs, the third type of RNAi discovered, function to maintaining genome integrity by suppressing transposon mobilization and performing germ-line imprinting. We have found that mitochondria play a role in generation of piRNAs via the action of a signaling enzyme anchored on the mitochondrial surface. We propose to increase our understanding of how a signal generated on the mitochondrial surface regulates this process, which may involve controlling how mitochondria and the RNA structures traffic through the cell on microtubules. If successful, the proposed research could facilitate the development of tools to broadly manipulate the epigenetic structure of genes and thus control their expression, might identify some causes of male infertility, and will present a potential therapeutic opportunity for a male contraceptive. It may also be important more broadly, as piRNAs are now being reported in many tissues.

描述（由申请人提供）：线粒体曾经被视为细胞的“简单”动力体，越来越多地被认为参与了许多不同的细胞生物学过程，这些过程涉及与内质网和诸如内质细胞细胞器相互作用的相互作用，例如内质网和质子膜。这些相互作用发生在线粒体表面的机械中，该机械在线粒体动力学（融合）的背景下对我们来说一直是我们的重点领域，并且对细胞外信号事件的响应响应能量变化。我们最近的工作以一种专门的RNA加工形式发现了线粒体的新作用，该作用似乎是在线粒体表面和并置的RNA颗粒之间的界面上进行的。更具体地说，我们已经将线粒体表面上的信号传导酶与PIRNA（第三种RNAi）的产生相关联，它是一种类似于p-bodies的电子致密结构，称为NUAGE。我们建议使用细胞生物学，在培养和动物模型方法中研究线粒体表面的脂质信号如何促进这种新发现的线粒体与RNA处理复合物之间的物理和功能相互作用，通过潜在地包括RNAS的运动蛋白调节的运输，加工花道菌和Microchuluulcriricria，这些机制可能包括潜在调节的运输机制。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，与男性不育具有相关性，并提供了一种新型男性避孕药的机会。但是，在线粒体表面募集和加工的其他类型的RNA募集是已知的，并且代表了更广泛的背景，在该环境中，这种新鉴定的途径可能很重要，包括与间充质干细胞，脑功能和心脏功能以及癌症有关。公共卫生相关性：动员转座子会导致包括癌症在内的遗传疾病。 PIRNA是发现的第三种RNAi，它通过抑制转座子动员和执行种系印迹来维持基因组完整性。我们发现线粒体通过锚定在线粒体表面的信号传导酶的作用在PIRNA中发挥作用。我们建议提高我们对线粒体表面上产生的信号的理解，从而调节该过程，这可能涉及控制线粒体和RNA结构如何通过微管上的细胞通过细胞流量。如果成功的话，拟议的研究可能会促进开发工具，以广泛操纵基因的表观遗传结构，从而控制其表达，可能会确定男性不育的某些原因，并为男性避孕药带来潜在的治疗机会。这也可能更广泛，因为现在在许多组织中报道了PIRNA。