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：
9264405
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 2020-04-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9264405
关键词：
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 Molecular Conformation Morphology Myocardial Ischemia Pathologic 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 Therapeutic Work base cell type clinically significant gain of function interest lipine loss of function member protein complex public health relevance sensor targeted treatment therapeutic evaluation 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）：该提案的重点是以下假设：线粒体表面的脂质信号通路促进了线粒体裂变的过程。我们已经发表了证据表明，脂肪蛋白1通过蛋白质中心的PA结合结构域募集到线粒体表面，将PA转换为相关的信号脂质脂质二酰基甘油（DAG），然后促进线粒体脂质体的脂质体。出乎意料的是，我们还发现Lipin 1在催化结构域中具有第二个隐秘的线粒体靶向序列，该催化域在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，该模型触发了构象的变化，以暴露第二个位点，该位点将靶向线粒体小管上的裂变位点靶向裂变位点，并以与DRP1的协作方式触发裂变，但也与DRP1部分独立，该方式是动态的蛋白质，最广泛地研究了裂变的物理调解剂。该主题具有直接的临床意义。线粒体裂变的操纵正在测试中，以在中风，心脏缺血和肺动脉高压中进行治疗。关于裂变过程基础机制的知识的越来越多将有助于开发这些方法。我们建议根据探索DAG如何与裂变机械的其他组件合作触发裂变，从而追求在Lipin 1-裂变故事中开发的感兴趣领域。此类问题包括定义蛋白质脂蛋白1与AT裂变位点或招募裂变相互作用的裂变位点，这些蛋白质是否在裂变过程中起作用，以及它们的功能还是裂变过程本身是由Lipin 1由DAG生产驱动的。与内质网（ER）和肌动蛋白细胞骨骼重组的关系，它们在裂变过程中起着重要作用。综上所述，这些研究将进一步了解我们对裂变基本机制的了解，并在开发靶向疾病的疗法方面具有实用性，并与此内在过程联系起来。

项目成果

期刊论文数量（12）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Role of mitochondrial lipids in guiding fission and fusion.

DOI：
10.1007/s00109-014-1237-z
发表时间：
2015-03
期刊：
JOURNAL OF MOLECULAR MEDICINE-JMM
影响因子：
4.7
作者：
Frohman, Michael A.
通讯作者：
Frohman, Michael A.

Deficiencies of the lipid-signaling enzymes phospholipase D1 and D2 alter cytoskeletal organization, macrophage phagocytosis, and cytokine-stimulated neutrophil recruitment.

DOI：
10.1371/journal.pone.0055325
发表时间：
2013
期刊：
PloS one
影响因子：
3.7
作者：
Ali WH;Chen Q;Delgiorno KE;Su W;Hall JC;Hongu T;Tian H;Kanaho Y;Di Paolo G;Crawford HC;Frohman MA
通讯作者：
Frohman MA

The phospholipase D superfamily as therapeutic targets.

DOI：
10.1016/j.tips.2015.01.001
发表时间：
2015-03
期刊：
TRENDS IN PHARMACOLOGICAL SCIENCES
影响因子：
13.8
作者：
Frohman, Michael A.
通讯作者：
Frohman, Michael A.

Coincident Phosphatidic Acid Interaction Restrains Drp1 in Mitochondrial Division.

DOI：
10.1016/j.molcel.2016.08.013
发表时间：
2016-09-15
期刊：
MOLECULAR CELL
影响因子：
16
作者：
Adachi, Yoshihiro;Itoh, Kie;Yamada, Tatsuya;Cerveny, Kara L.;Suzuki, Takamichi L.;Macdonald, Patrick;Frohman, Michael A.;Ramachandran, Rajesh;Iijima, Miho;Sesaki, Hiromi
通讯作者：
Sesaki, Hiromi

A C-Terminal Transmembrane Anchor Targets the Nuage-Localized Spermatogenic Protein Gasz to the Mitochondrial Surface.