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

• 批准号: 7747970
• 负责人: Michael A. Frohman
• 金额: $ 30.83万
• 依托单位: STATE UNIVERSITY NEW YORK STONY BROOK
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-01-01 至 2012-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7747970
• 关键词: 1,2-diacylglycerol; Acute; Agonist; Biochemical; Biological Assay; Biology; Cells; Chemicals; Confocal Microscopy; Development; Diabetes Mellitus; Diglycerides; Disease; Environment; Enzymes; Face; Failure; Generations; Glucose; Human; Lead; Link; Lipids; Lipodystrophy; Location; Methods; Mitochondria; Molecular; Morphology; Mus; Mutation; Neurodegenerative Disorders; Neurons; Non-Insulin-Dependent Diabetes Mellitus; Organelles; Outer Mitochondrial Membrane; Phosphatidic Acid; Phosphoric Monoester Hydrolases; Physiological; Presynaptic Terminals; Process; Production; Proteomics; Pyruvate Metabolism Pathway; Reader; Regulation; Role; Signal Pathway; Signal Transduction; Site; Stimulus; Surface; Time; Transfection; extracellular; human disease; in vivo; insight; insulin signaling; lipine; novel; novel therapeutic intervention; public health relevance; research study; response; tissue culture; tool development; unpublished works

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 Our more recent unpublished work has connected the production of this signaling lipid on the mitochondrial surface to the generation of an inter-related signaling lipid, Diacylglycerol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

描述（由申请人提供）：线粒体是动态细胞器，在许多方面自主起作用，可以通过葡萄糖（丙酮酸）代谢产生能量，通过融合和裂变进行形态学变化，并在细胞周围移动。但是，这些过程也对从细胞外环境传递的信号有响应。例如，胰岛素向细胞发出信号以上调线粒体融合并改变能量的产生。融合和裂变的调节也是对神经营养刺激的响应在神经元中正确移动线粒体的关键。这些基本过程（当异常）引起许多类型的人类疾病，包括神经退行性疾病和糖尿病。细胞外信号传导与线粒体反应之间的联系仅部分理解。我们以前在线粒体融合中发现了信号脂质磷脂酸（PA）的新作用[11]。我们最近未发表的工作将这种信号脂质在线粒体表面的产生与相互关联的信号脂质二酰基甘油（DAG）的产生有关。 PA可以通过脂质磷酸酶Lipin 1转换为DAG，当表面PA水平升高时，我们发现它已易位到线粒体。已证明小鼠和人类中的脂肪1突变会引起与II型糖尿病相似的脂肪营养不良的形式。综上所述，这些发现和其他发现表明，在胰岛素信号传导和其他细胞外信号通路的情况下，线粒体表面上的脂质信号的产生可能调节线粒体融合，裂变和能量。在此应用程序中，我们建议在AIM 1中表征线粒体外膜的外部表面，是涉及PA和DAG的脂质信号传导的平台，包括分析控制其生产和消除的关键酶的募集，以及对它们上调它们的生理信号通路的识别。在AIM 2中，我们将研究这些信号脂质在细胞外信号导致线粒体融合，裂变和能量产生的调节中的作用。到拟议的实验结束时，我们将在糖尿病的背景下在细胞外激动剂，线粒体表面的脂质信号和线粒体生理反应之间牢固建立联系。由于这些信号传导步骤中的许多代表了“可吸毒”目标，因此了解对这些基本过程的控制可能会导致糖尿病和其他疾病环境中新型的治疗方法。公共卫生相关性线粒体是细胞的“动力”，从葡萄糖的化学加工中产生能量。线粒体在大部分时间内都自主功能，但也对从电池外部发送的信号响应，这些信号指导它们以提高其能源产生水平，部分是通过增加大小，并移至能量需求最急性的单元格中。线粒体对这些信号的反应能力的失败并在细胞中必要的位置产生足够的能量会导致几种类型的人类疾病，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响应联系起来的分子机制，以期获得洞察力，这些见解能够在不同的疾病环境下进行药理学对它们进行药理操作的能力。