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）：本提案关注线粒体表面脂质信号通路促进线粒体裂变过程的假设。我们已经发表的证据表明，脂质磷脂酸（PA）通过蛋白质中心的PA结合结构域将酶Lipin 1募集到线粒体表面，将PA转化为相关的信号脂质二酰基甘油（DAG），然后促进线粒体裂变。出乎意料的是，我们还发现，Lipin 1在催化结构域中含有第二个隐藏的线粒体靶向序列，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结合会触发构象变化，从而暴露出第二个位点，这个位点强烈地以线粒体小管上的裂变位点为目标，并以与Drp1（一种被广泛研究为裂变物理介质的动态样蛋白）协同但也部分独立的方式强烈地触发裂变。本课题具有直接的临床意义。操纵线粒体裂变正在测试用于中风、心脏缺血和肺动脉高压的治疗应用；增加关于裂变过程背后机制的知识将有助于这些方法的发展。我们建议在探索DAG如何与裂变机制的其他组成部分协作触发裂变的基础上，在Lipin 1 -裂变故事的背景下发展兴趣领域。这些问题包括确定在裂变位点与Lipin 1相互作用的蛋白质或通过产生DAG而招募到裂变位点的蛋白质，这些蛋白质是否在裂变过程中起作用，以及它们的功能或裂变过程本身是否由Lipin 1产生DAG驱动。我们还将研究其他脂素酶家族成员在裂变中的作用，探讨脂素如何被招募到裂变位点，以及它与内质网（ER）和肌动蛋白细胞骨架重组的关系，它们在裂变过程中起着重要作用。综上所述，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一内在过程有关的疾病的治疗方法。