Lipid signaling pathways regulating mitochondrial morphology, energetics, and mov

摘要 线粒体是动态的细胞器，其在许多方面自主地发挥功能，以通过线粒体产生能量。 葡萄糖（丙酮酸）代谢，通过融合和裂变进行形态变化，并在细胞内移动。 cell.然而，这些过程也响应于从细胞外环境递送的信号; 例如，胰岛素信号细胞上调线粒体融合和改变能量的产生。的 融合和分裂的调节也是将线粒体适当地移动到神经元中突触末端的关键， 对神经营养刺激的反应。这些基本的过程，当异常时，会导致许多类型的人类疾病。 包括神经变性疾病和糖尿病的疾病。 细胞外信号和线粒体反应之间的联系只被部分理解。我们 先前揭示了信号脂质磷脂酸（PA）在线粒体融合中的新作用[11]。我们 最近未发表的工作已经将这种信号脂质在线粒体表面的产生联系起来， 产生相互关联的信号脂质，二酰基甘油（DAG）。PA可以通过 脂质磷酸酶Lipin 1，我们发现当表面PA水平增加时，它会转移到线粒体 那里小鼠和人类中的Lipin 1突变已被证明会导致一种形式的脂肪营养不良， 与II型糖尿病相似。综上所述，这些和其他研究结果表明，脂质的产生 线粒体表面上的信号可以调节线粒体融合、分裂和线粒体中的能量学。 胰岛素信号传导和其他细胞外信号传导途径的背景。 在本申请中，我们在目的1中提出表征线粒体外膜的外表面， 膜作为涉及PA和DAG的脂质信号传导的平台，包括分析 控制其产生和消除的关键酶，以及生理信号的鉴定 上调它们的途径。在目标2中，我们将研究这些信号脂质在调控中的作用。 作为细胞外信号传导的结果，线粒体融合、裂变和能量产生。 到实验结束时，我们将牢固地建立细胞外 激动剂，线粒体表面的脂质信号传导，以及在这种情况下的线粒体生理反应 糖尿病由于这些信号步骤中的许多都代表了“可药物化”的目标， 这些基本过程可以为糖尿病和其他疾病的新的治疗方法提供线索。 疾病设置。

Abstract 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 Our more recent unpublished work has connected the production of this signaling lipid on the mitochondrial surface to the generation of an inter-related signaling lipid, Diacylglycerol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.