Lipid-signaling pathways regulating mitochondrial morphology, energetics, and mov

该建议的重点是假设线粒体表面的脂质信号通路 促进线粒体分裂的过程。我们已经发表的证据表明，脂蛋白1酶，这是 脂质磷脂酸（PA）通过中心的PA结合结构域募集到线粒体表面 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，其表现出高度特异性的亚细胞定位到未来的位点 裂变事件这导致了一个模型，即与PA结合会引发构象变化，从而暴露出第二个 该位点热切地靶向线粒体小管上的裂变位点，并在协同作用中强烈地触发裂变。 但也部分独立的方式与Drp 1，最广泛研究的动态样蛋白质的物理 裂变的媒介。本课题具有直接的临床意义。线粒体分裂的操纵 测试用于治疗中风，心脏缺血和肺动脉高压;增加 关于裂变过程的基本机制的知识将有助于这些方法的发展。我们 我建议继续研究在Lipin 1裂变故事背景下开发的感兴趣的领域 探索DAG如何与裂变机制的其他组件合作引发裂变。 这些问题包括确定Lipin 1在裂变位点与之相互作用的蛋白质或在裂变位点的招募 通过DAG的产生，这些蛋白质是否在裂变过程中发挥作用，以及它们是否 功能或裂变过程本身由Lipin 1的DAG生产驱动。我们还将研究 Lipin酶家族的其他成员在裂变中，探索Lipin是如何被招募到裂变位点， 与内质网（ER）和肌动蛋白细胞骨架重组的关系，这两种结构在细胞骨架重组中起重要作用 在裂变过程中。总之，这些研究将进一步加深我们对潜在机制的认识。 裂变，并在开发靶向疾病的治疗方法中具有实用性， 过程

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.