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: 8018063
• 负责人: Michael A. Frohman
• 金额: $ 30.62万
• 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/8018063
• 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; Health; 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signaling; lipine; novel; novel therapeutic intervention; research study; response; tissue culture; tool development; unpublished works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 Our more recent unpublished work has connected the production of this signaling lipid on the mitochondrial surface to the generation of an inter-related signaling lipid, Diacylglycerol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，其在许多方面自主发挥功能，通过葡萄糖（丙酮酸盐）代谢产生能量，通过融合和分裂发生形态学变化，并在细胞内移动。然而，这些过程也响应于从细胞外环境传递的信号;例如，胰岛素信号细胞上调线粒体融合并改变能量的产生。融合和分裂的调节也是将线粒体适当地移动到神经元中的突触末端以响应神经营养刺激的关键。这些基本过程，当异常时，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理解。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已经将线粒体表面上这种信号脂质的产生与相互关联的信号脂质二酰基甘油（DAG）的产生联系起来。PA可以通过脂质磷酸酶Lipin 1转化为DAG，我们发现当表面PA水平增加时，Lipin 1易位到线粒体。在小鼠和人类中的Lipin 1突变已被证明会导致一种与II型糖尿病相似的脂肪代谢障碍。总而言之，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传导和其他细胞外信号传导途径的背景下调节线粒体融合、裂变和能量学。在本申请中，我们在目的1中提出将线粒体外膜的外表面表征为涉及PA和DAG的脂质信号传导的平台，包括控制其产生和消除的关键酶的募集的分析，以及上调它们的生理信号传导途径的鉴定。在目标2中，我们将研究这些信号脂质在线粒体融合，分裂和能量产生的调节中的作用，作为细胞外信号的结果。在所提出的实验结束时，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和糖尿病背景下的线粒体生理反应之间的联系。由于这些信号步骤中的许多都代表了“可药物化”的目标，因此深入了解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。线粒体是细胞的“发电站”，从葡萄糖的化学加工中产生能量。线粒体在大部分时间里都是自主发挥作用的，但也会对细胞外发出的信号做出反应，这些信号引导线粒体增加能量产生水平，部分是通过增加尺寸，并移动到细胞内能量需求最严重的部位。线粒体不能适当地响应这些信号并在细胞中的必要位置产生足够量的能量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对它们进行连续操作的能力。