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Characterization of Mitochondrial GTP as an Intramitochondrial Metabolic Signal

线粒体 GTP 作为线粒体内代谢信号的表征

基本信息

批准号：
7673628
负责人：
Richard G Kibbey
金额：
$ 15.16万
依托单位：
YALE UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2008
资助国家：
美国
起止时间：
2008-09-01 至 2013-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7673628
关键词：
ATP Synthesis Pathway Accounting Affect Award Back Beta Cell Blood Glucose Ca(2+)-Transporting ATPase Calcium Calcium Channel Calcium Oscillations Calcium Signaling Carbon Cell membrane Cells Charge Chemicals Childhood Citric Acid Cycle Clinical Investigator Coupled Couples Coupling Cytoplasmic Granules Cytosol Data Dependence Development Diabetes Mellitus Disease Electron Transport Energy Metabolism Ensure Enzymes Epidemic Event Failure Functional disorder Gel Gene Silencing Glucose Glutamate Dehydrogenase Guanosine Triphosphate Hydrogen Hyperammonemia Hyperinsulinism Hypoglycemia In Vitro Individual Insulin Investigation Islets of Langerhans Isotope Labeling Lead Link Location Malates Measurable Mediator of activation protein Medical Membrane Membrane Potentials Metabolic Metabolism Methods Mitochondria Modeling Molecular Monitor Mouse Cell Line Mus Mutation NADP Non-Insulin-Dependent Diabetes Mellitus Nucleotides Organelles Oxidation-Reduction Oxidative Phosphorylation Oxygen Consumption Pancreas Pathogenesis Pathway interactions Phenotype Phosphate Buffer Principal Investigator Process Production Protein Isoforms Pump Pyruvate Carboxylase Rattus Regulation Research Research Personnel Role Second Messenger Systems Secretory Vesicles Seminal Serum Signal Transduction Small Interfering RNA Specificity Succinate-CoA Ligases Tissues Transgenic Mice Transgenic Organisms Work calcium phosphate cost design dicarboxylate driving force economic cost enzyme activity experience glucose metabolism in vivo inorganic phosphate insight insulin secretion islet mitochondrial dysfunction mitochondrial membrane novel oxidation prevent programs second messenger sensor social tool uptake voltage

项目摘要

DESCRIPTION (provided by applicant): Type-2 diabetes (T2DM), a disease that now of epidemic proportions across the world with enormous social and medical costs. Failure of (-cells to adequately sense glucose and release insulin is the critical event leading to diabetes. Mitochondrial metabolism of (-cells senses blood glucose levels and thus a seminal question to understanding glucose stimulated insulin secretion is how mitochondrial fuel metabolism is "sensed." Thus the molecular mechanisms by which mitochondria "sense" metabolic flux are essential to understand the pathophysiology of T2DM. From observations in a pediatric disorder of hyperinsulinemic hypoglycemia I hypothesized that mitochondrial GTP (mtGTP) produced by the TCA cycle enzyme Succinyl CoA Synthetase (SCS) was an essential molecular signal that coupled mitochondrial metabolism to insulin secretion. A key insight was that mtGTP, unlike ATP, is an intramitochondrial signal produced stoichiometrically by each turn of the TCA cycle. By virtue of its tight coupling rates of TCA cycle oxidation, mtGTP might serve as a molecular tachometer for the TCA cycle. By altering mtGTP synthesis rates via gene silencing, a direct relationship between mtGTP and insulin secretion was observed. Surprisingly, mtGTP dramatically altered the function of mitochondria from ATP-synthesis to organelles that harness the energy of metabolism to pump calcium in and out of the mitochondria. Furthermore, the mtGTP signal provoked insulin secretion via a non-canonical KATP-independent mechanism by was dependent upon cytosolic calcium increases. Because of its isolated location, mtGTP is likely to be a very early signal dependent upon other mediators to transmit its signal to the secretory vesicles in the cytosol. Here I propose to: 1) To assess the role of mtGTP in metabolism and insulin secretion by over-expression of SCS isoforms. 2) To assess mtGTP regulation of mitochondrial anaplerosis. 3) To assess how mtGTP converts mitochondria from ATP synthesis to transporting calcium and phosphate. The projects outlined in this proposal are designed to answer not only essential questions about diabetes, but also to ensure my development as a well rounded clinical investigator and support from this award will provide an intensive, supervised research experience that is necessary to be an independent researcher and competitive at the R01 level. As fuel sensing is the essential mechanism that leads to insulin secretion, this signal will have profound implications for understanding and treatment of T2DM.

描述（由申请人提供）：