Lipid-signaling pathways regulating mitochondrial morphology, energetics, and mov

脂质信号通路调节线粒体形态、能量学和 mov

基本信息

批准号：
8630384
负责人：
Michael A. Frohman
金额：
$ 31.6万
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：
2009
资助国家：
美国
起止时间：
2009-01-01 至 2018-04-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8630384
关键词：
1,2-diacylglycerol Actins Address Affect Area Award Binding Binding Sites Blood Vessels C-terminal Cardiac Catalytic Domain Cell membrane Cell physiology Cells Cleaved cell Clinical Collaborations Cytoplasm Cytoskeletal Modeling Cytoskeleton Data Development Diglycerides Disease Dynamin Endoplasmic Reticulum Endosomes Enzymes Event Exhibits Family Frequencies Funding Future Generations Health Heart Homo Inner mitochondrial membrane Ischemia Knowledge Lamins Learning Length Lipids Malignant neoplasm of lung Mediator of activation protein Mind Mitochondria Mitosis Modeling Morphology Phenotype Phosphatidate Phosphatase Phosphatidic Acid Play Process Production Proliferating Protein Isoforms Proteins Proteomics Publishing Pulmonary Hypertension Recruitment Activity Regulation Reporting Role Signal Pathway Signal Transduction Site Stroke Surface Testing Therapeutic Work base cell type clinically significant gain of function interest lipine loss of function member protein complex public health relevance sensor therapy development

项目摘要

This proposal focuses on the hypothesis that a lipid signaling pathway on the surface of the mitochondria facilitates the process of mitochondrial fission. We have published evidence that the enzyme Lipin 1, which is recruited to the mitochondrial surface by the lipid phosphatidic acid (PA) via a PA-binding domain in the center of the protein, converts the PA to the related signaling lipid diacylglycerol (DAG), which then promotes mitochondrial fission. Unexpectedly, we also found that Lipin 1 harbors a second, cryptic mitochondrial targeting sequence in the catalytic domain that exhibits highly-specific subcellular localization to sites of future fission events. This led to a model that binding to PA triggers a conformational change to expose the second site which avidly targets fission sites on the mitochondrial tubule and robustly triggers fission in a collaborative but also partially independent manner with Drp1, the dynamic-like protein most widely studied as the physical mediator of fission. This topic has direct clinical significance. Manipulation of mitochondrial fission is being tested for therapeutic application in stroke, cardiac ischemia, and pulmonary hypertension; increased knowledge about mechanisms underlying the fission process will aid in development of these approaches. We propose to pursue areas of interest that have been developed in the context of the Lipin 1 - fission story based on exploration of how DAG triggers fission in collaboration with other components of the fission machinery. Such questions include defining the proteins Lipin 1 interacts with at fission sites or recruits to the fission sites through the production of DAG, whether these proteins have roles in the fission process, and whether their function or the fission process itself is driven by DAG production by Lipin 1. We will also examine roles for other members of the Lipin enzyme family in fission, explore how Lipin is recruited to fission sites, and its relationship to the endoplasmic reticulum (ER) and actin cytoskeletal reorganization, which play important roles in the fission process. Taken together, these studies will further our knowledge of the mechanisms underlying fission and be of utility in the development of therapies targeting diseases with connections to this intrinsic process.

该提案的重点是线粒体表面的脂质信号通路的假设促进线粒体裂变过程。我们已经发表了证据表明脂质酶 1（Lipin 1）脂质磷脂酸 (PA) 通过中心的 PA 结合结构域募集至线粒体表面蛋白质的结构，将 PA 转化为相关的信号脂质二酰甘油 (DAG)，然后促进线粒体裂变。出乎意料的是，我们还发现 Lipin 1 含有第二个神秘的线粒体催化结构域中的靶向序列对未来位点表现出高度特异性的亚细胞定位裂变事件。这导致了一个模型，与 PA 结合会触发构象变化以暴露第二个该位点热衷于靶向线粒体小管上的裂变位点，并在协作中强烈触发裂变但也与 Drp1 部分独立，Drp1 是最广泛研究的动态蛋白，作为物理裂变的中介体。本课题具有直接的临床意义。线粒体裂变的操纵正在测试了中风、心肌缺血和肺动脉高压的治疗应用；增加有关裂变过程背后机制的知识将有助于开发这些方法。我们建议探索在 Lipin 1 背景下开发的感兴趣领域 - 基于裂变故事探索 DAG 如何与裂变机制的其他组件协作触发裂变。这些问题包括定义 Lipin 1 在裂变位点相互作用或招募到裂变位点的蛋白质通过 DAG 的产生，这些蛋白质是否在裂变过程中发挥作用，以及它们是否功能或裂变过程本身是由 Lipin 1 的 DAG 生产驱动的。我们还将研究以下角色：裂变中脂质酶家族的其他成员，探索脂质如何被招募到裂变位点，及其与内质网（ER）和肌动蛋白细胞骨架重组的关系，它们发挥着重要作用在裂变过程中。总而言之，这些研究将进一步加深我们对潜在机制的了解裂变并可用于开发针对与这种内在联系的疾病的疗法过程。