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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.

这一建议集中在线粒体表面脂质信号通路的假设