Metabolic regulation via intramitochondrial sAC

通过线粒体内 sAC 进行代谢调节

• 批准号: 8695560
• 负责人: JOCHEN BUCK
• 金额: $ 37.8万
• 依托单位: WEILL MEDICAL COLL OF CORNELL UNIV
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-07-15 至 2018-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8695560
• 关键词: ATP Synthesis Pathway; Ablation; Acute; Adenylate Cyclase; Affect; Animals; Astrocytes; Bicarbonates; Biochemical; Bioenergetics; Brain; Calcium; Carbon Dioxide; Catechol Estrogens; Cell membrane; Cells; Chronic; Cilia; Citric Acid Cycle; Communication; Complex; Cues; Cultured Cells; Cyclic AMP; Cyclic AMP-Dependent Protein Kinases; Cytoplasm; Data; Defect; Dependence; Diabetes Mellitus; Electron Transport; Electrons; Embryo; Enzymes; Epididymis; Equilibrium; Exhibits; Eye; Fertility; Fibroblasts; Frequencies; Functional disorder; Glucose; Glucose tolerance test; Health; Heterotrimeric GTP-Binding Proteins; Homeostasis; Hormones; Insulin; KRP protein; Kidney; Link; Mediating; Metabolic; Metabolic Diseases; Metabolic stress; Metabolism; Mitochondria; Mus; NADH; Neurons; Neurotransmitters; Nutrient; Nutritive Value; Oxidative Phosphorylation; Pancreas; Pathway interactions; Phenotype; Physiologic Intraocular Pressure; Physiological; Positioning Attribute; Production; Protons; Reactive Oxygen Species; Regulation; Relative (related person); Resources; Role; Second Messenger Systems; Signal Pathway; Signal Transduction; Source; System; Tissues; airway epithelium; blood glucose regulation; carbonate dehydratase; cell motility; detection of nutrient; electron donor; extracellular; feeding; glucose metabolism; glucose sensor; in vivo; inhibitor/antagonist; male; oxidative damage; respiratory; response; second messenger; sensor; sperm cell; wasting

DESCRIPTION (provided by applicant): It has become widely accepted that cAMP acts locally, in independently regulated signaling microdomains. Soluble adenylyl cyclase (sAC) is molecularly, biochemically and functionally distinct from the other known mammalian sources of cAMP, the transmembrane adenylyl cyclases (tmACs). While tmACs are positioned at the plasma membrane where they are regulated by heterotrimeric G proteins in response to extracellular cues such as hormones and neurotransmitters, sAC is distributed throughout the cytoplasm and in intracellular compartments, including mitochondria, where it is poised to provide the second messenger regulating the intracellular and intra-organellar targets of cAMP. Inside mitochondria, sAC-generated cAMP regulates components of the electron transport chain (ETC), increasing electron flux and the overall rate of ATP synthesis. This intramitochondrial sAC-cAMP signaling pathway linking cellular nutrient utilization with energy production defines a mechanism of short-term modulation of oxidative phosphorylation which allows the cell's respiratory machinery to respond to transient changes in nutritional availability, environmental conditions, and energy requirements. In this application, we propose to elucidate the physiological significance of this pathway. We propose to (1) determine the consequences of both chronic and acute abrogation of the intramitochondrial sAC-cAMP pathway in cultured cells using pharmacological inhibitors and cells derived from sAC-C1 KO mice; and (2) discern which of the known metabolic phenotypes seen in sAC-C1 KO mice are caused by abrogation of the intramitochondrial sAC-cAMP pathway. Understanding the role of this pathway is likely to have important implications for cell intrinsic nutrient sensing, diabetes, and metabolism in general, and it will reveal the functional significance of this intracellular cAMP microdomain.

描述（由申请人提供）：人们普遍认为，cAMP 在独立调节的信号微域中局部发挥作用。可溶性腺苷酸环化酶 (sAC) 在分子、生物化学和功能上都不同于其他已知的哺乳动物来源的 cAMP，即跨膜腺苷酸环化酶 (tmAC)。 tmAC 位于质膜上，并受到异源三聚体 G 蛋白的调节，以响应激素和神经递质等细胞外信号，而 sAC 分布在整个细胞质和细胞内区室中，包括线粒体，在那里它准备提供第二信使调节 cAMP 的细胞内和细胞器内靶标。在线粒体内部，sAC 生成的 cAMP 调节电子传递链 (ETC) 的组成部分，增加电子通量和 ATP 合成的总体速率。这种线粒体内 sAC-cAMP 信号通路将细胞营养利用与能量产生联系起来，定义了氧化磷酸化的短期调节机制，使细胞的呼吸机制能够对营养可用性、环境条件和能量需求的瞬时变化做出反应。在本申请中，我们建议阐明该途径的生理意义。我们建议 (1) 使用药理学抑制剂和源自 sAC-C1 KO 小鼠的细胞确定培养细胞中线粒体内 sAC-cAMP 通路慢性和急性废除的后果； (2) 辨别 sAC-C1 KO 小鼠中已知的哪些代谢表型是由线粒体内 sAC-cAMP 通路的废除引起的。了解该途径的作用可能对细胞内在营养感应、糖尿病和一般代谢产生重要影响，并将揭示该细胞内 cAMP 微结构域的功能意义。