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：
8901194
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/8901194
关键词：
1,2-diacylglycerol Actins Address Affect Area Award Binding Binding Sites Blood Vessels C-terminal 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 Myocardial Ischemia 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 sensor targeted sequencing targeted treatment therapy development

项目摘要

DESCRIPTION (provided by applicant): 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 throgh 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.

描述（由申请人提供）：该提案重点关注线粒体表面的脂质信号传导途径促进线粒体裂变过程的假设。我们发表的证据表明，脂质磷脂酸 (PA) 通过蛋白质中心的 PA 结合结构域将脂质 1 酶募集到线粒体表面，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 在催化结构域中包含第二个神秘的线粒体靶向序列，该序列对未来裂变事件的位点表现出高度特异性的亚细胞定位。这导致了一个模型，即与 PA 结合触发构象变化，暴露第二个位点，该位点热衷于靶向线粒体小管上的裂变位点，并与 Drp1（研究最广泛的动态样蛋白）以协作但部分独立的方式强力触发裂变。作为裂变的物理介质。本课题具有直接的临床意义。正在测试线粒体裂变的操纵在中风、心肌缺血和肺动脉高压方面的治疗应用；增加对裂变过程背后机制的了解将有助于开发这些方法。我们建议基于对 DAG 如何与裂变机制的其他组件协作触发裂变的探索，探索在 Lipin 1 裂变故事背景下开发的感兴趣领域。这些问题包括定义Lipin 1在裂变位点相互作用的蛋白质或通过DAG的产生招募到裂变位点的蛋白质，这些蛋白质是否在裂变过程中发挥作用，以及它们的功能或裂变过程本身是否由DAG的产生驱动Lipin 1. 我们还将研究 Lipin 酶家族其他成员在裂变中的作用，探讨 Lipin 如何被招募到裂变位点，及其与内质网的关系（ER）和肌动蛋白细胞骨架重组，在裂变过程中发挥重要作用。总而言之，这些研究将进一步加深我们对裂变机制的了解，并有助于开发针对与这一内在过程相关的疾病的疗法。