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

• 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
• 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

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.

这一建议侧重于一种假设，即线粒体表面的一条脂质信号通路 促进线粒体分裂的过程。我们已经发表的证据表明，脂酶1，也就是 脂质磷脂酸(PA)通过中央的PA结合域被募集到线粒体表面 将PA转化为相关的信号脂二酰甘油(DAG)，然后促进 线粒体分裂。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，显示出对未来位点具有高度特异性的亚细胞定位 裂变事件。这导致了一种与PA结合的模型，该模型触发构象变化以暴露第二个 一种以线粒体管上的分裂位点为靶点，并在协作的 但也与Drp1部分独立，Drp1是一种动态类蛋白质，被广泛研究为物理 核裂变的调解人。本课题具有直接的临床意义。对线粒体分裂的操纵正在被 对中风、心肌缺血和肺动脉高压的治疗应用测试；增加 对裂变过程潜在机制的了解将有助于这些方法的发展。我们 建议追求在脂类1-裂变故事的背景下开发的感兴趣的领域 关于DAG如何与裂变机械的其他组件协作触发裂变的探索。 这些问题包括定义脂蛋白1在裂变部位与哪些蛋白质相互作用或招募哪些蛋白质进入裂变部位。 通过DAG的产生，这些蛋白质是否在裂变过程中发挥作用，以及它们的 功能或裂变过程本身是由脂蛋白1产生的DAG驱动的。我们还将研究 在分裂中脂酶家族的其他成员，探索脂类如何被招募到分裂部位，以及它的 与内质网和肌动蛋白细胞骨架重组的关系，这两个因素发挥着重要作用 在裂变过程中。综上所述，这些研究将加深我们对潜在机制的了解 裂变和BE在针对与此内在联系的疾病的治疗方法的开发中是有用的 进程。