Lipid signaling pathways regulating mitochondrial morphology, energetics, and mov

描述(申请人提供)：线粒体是动态细胞器，在许多方面发挥自主功能，通过葡萄糖(丙酮酸)代谢产生能量，通过融合和分裂经历形态变化，并在细胞内移动。然而，这些过程也对细胞外环境传递的信号做出反应；例如，胰岛素向细胞发出信号，上调线粒体融合并改变能量的产生。融合和分裂的调控也是线粒体在神经营养刺激下正确移动到神经元突触终末的关键。当这些基本过程异常时，会导致许多类型的人类疾病，包括神经退行性疾病和糖尿病。细胞外信号和线粒体反应之间的联系只被部分了解。我们之前发现了信号脂质磷脂酸(PA)在线粒体融合中的新作用[11]。我们最近未发表的工作将线粒体表面这种信号脂的产生与相互关联的信号脂二酰甘油(DAG)的产生联系起来。PA可以被脂磷酸酶Lipin 1转化为DAG，我们发现当线粒体表面PA水平增加时，Lipin 1易位到线粒体。小鼠和人类的脂类1基因突变已被证明会导致一种类似于II型糖尿病的脂肪营养不良。综上所述，这些和其他发现表明，线粒体表面脂质信号的产生可能在胰岛素信号和其他细胞外信号途径的背景下调节线粒体的融合、分裂和能量学。在这一应用中，我们在目标1中建议将线粒体外膜的外部表面描述为涉及PA和DAG的脂质信号的平台，包括分析控制其产生和消除的关键酶的招募，以及鉴定上调它们的生理信号通路。在目标2中，我们将研究这些信号脂在细胞外信号对线粒体融合、分裂和能量产生的调节中所起的作用。到拟议的实验结束时，我们将在细胞外激动剂、线粒体表面的脂质信号和糖尿病背景下的线粒体生理反应之间建立牢固的联系。由于这些信号步骤中的许多都是“可用药”的靶点，因此深入了解对这些基本过程的控制可能会为糖尿病和其他疾病的治疗提供新的方法。与公共健康相关的线粒体是细胞的“发动机”，从葡萄糖的化学处理中产生能量。线粒体在很多时候都是自主运作的，但也会对细胞外发出的信号做出反应，这些信号指示它们增加能量产生水平，部分是通过增加大小，并转移到细胞内能量需求最强烈的位置。线粒体不能对这些信号做出适当的反应，并在细胞中必要的位置产生足够的能量，这会导致多种人类疾病，包括II型糖尿病和神经退行性疾病。我们正在研究将外部信号与线粒体反应联系起来的分子机制，希望获得能够在不同疾病背景下从药物上操纵它们的见解。

DESCRIPTION (provided by applicant): Mitochondria are dynamic organelles that function autonomously in many respects to produce energy via glucose (pyruvate) metabolism, undergo morphological change through fusion and fission, and move about the cell. However, these processes are also responsive to signals delivered from the extracellular environment; for example, insulin signals cells to upregulate mitochondrial fusion and alter the production of energy. The regulation of fusion and fission is also key for moving mitochondria properly to synaptic terminals in neurons in response to neurotrophic stimuli. These fundamental processes, when abnormal, cause many types of human disorders including neurodegenerative disease and diabetes. The links between extracellular signaling and mitochondrial responses are understood only in part. We previously uncovered a new role for the signaling lipid Phosphatidic Acid (PA) in mitochondrial fusion [11]. Our more recent unpublished work has connected the production of this signaling lipid on the mitochondrial surface to the generation of an inter-related signaling lipid, Diacylglycerol (DAG). PA can be converted to DAG by the lipid phosphatase Lipin 1, which we have found translocates to mitochondria when surface PA levels increase there. Lipin 1 mutations in mice and humans have been shown to cause a form of lipodystrophy with similarities to Type II diabetes. Taken together, these and other findings suggest that the generation of lipid signals on the surface of the mitochondria may regulate mitochondrial fusion, fission, and energetics in the context of insulin signaling and other extracellular signaling pathways. In this application, we propose in Aim 1 to characterize the external face of the mitochondrial outer membrane as a platform for lipid signaling involving PA and DAG, including analysis of the recruitment of the key enzymes that control their production and elimination, and identification of the physiological signaling pathways that upregulate them. In Aim 2, we will investigate the roles of these signaling lipids in the regulation of mitochondrial fusion, fission, and energy production as a consequence of extracellular signaling. By the end of the proposed experiments, we will have firmly established connections between extracellular agonists, lipid signaling at the mitochondrial surface, and mitochondrial physiological responses in the context of diabetes. Since many of these signaling steps represent "drugable" targets, gaining insight into the control of these fundamental processes may provide leads to novel therapeutic approaches in diabetes and other disease settings. PUBLIC HEALTH RELEVANCE Mitochondria are the "powerhouse" of the cell, generating energy from the chemical processing of glucose. Mitochondria function autonomously much of the time, but are also responsive to signals send from outside of the cell that direct them to increase their level of energy production, in part by increasing in size, and to move to sites within the cell where the energy demand is most acute. Failures in the ability of mitochondria to respond appropriate to these signals and generate adequate amounts of energy at the necessary location in the cell results in several types of human disease including Type II diabetes and neurodegenerative diseases. We are studying the molecular mechanisms that link the external signals to the mitochondrial responses, in hopes of obtaining insights that lead to the ability to pharmacologically manipulate them in the context of different disease settings.