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: 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
• 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

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）：该提案侧重于线粒体表面上的脂质信号传导途径促进线粒体分裂过程的假设。我们已经发表的证据表明，酶Lipin 1，这是招募到线粒体表面的脂质磷脂酸（PA）通过PA结合结构域的中心的蛋白质，PA转换为相关的信号脂质甘油二酯（DAG），然后促进线粒体分裂。出乎意料的是，我们还发现Lipin 1在催化结构域中含有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，结合PA触发构象变化，暴露第二个网站，它贪婪地靶向线粒体小管上的裂变位点，并以协同但部分独立的方式与Drp 1（最广泛研究的动态蛋白质）一起强烈触发裂变。本课题具有直接的临床意义。线粒体分裂的操作正在测试中的中风，心肌缺血和肺动脉高压的治疗应用;增加有关分裂过程的机制的知识将有助于这些方法的发展。我们建议追求的兴趣领域，已开发的背景下，Lipin 1裂变的故事的基础上探索DAG如何触发裂变与其他组件的裂变机制。这些问题包括定义Lipin 1在分裂位点相互作用的蛋白质或通过DAG的产生招募到分裂位点，这些蛋白质是否在分裂过程中发挥作用，以及它们的功能或分裂过程本身是否由Lipin 1的DAG产生驱动。我们还将研究Lipin酶家族的其他成员在裂变中的作用，探索Lipin是如何被招募到裂变位点的，以及它与内质网（ER）和肌动蛋白细胞骨架重组的关系，这些在裂变过程中发挥着重要作用。总之，这些研究将进一步加深我们对裂变机制的认识，并有助于开发针对与这种内在过程有关的疾病的治疗方法。