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L-2-Hydroxyglutarate and Metabolic Remodeling in Hypoxia

L-2-羟基戊二酸和缺氧中的代谢重塑

基本信息

批准号：
10521282
负责人：
Joseph Loscalzo
金额：
$ 69.01万
依托单位：
BRIGHAM AND WOMEN'S HOSPITAL
依托单位国家：
美国
项目类别：
财政年份：
2020
资助国家：
美国
起止时间：
2020-12-20 至 2024-11-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10521282
关键词：
6-Phosphofructo-2-kinase Address Adverse effects Back Biochemical Brain Hypoxia-Ischemia Buffers Cardiac Myocytes Cardiovascular Diseases Cardiovascular system Cell Hypoxia Cell physiology Cells Citric Acid Cycle Cultured Cells Cytoprotection Data Dependence Echocardiography Endothelial Cells Endothelium Eukaryota Fructose-2,6-bisphosphatase Functional disorder G6PD gene GPX3 gene Generations Genetic Glucose Glutathione Disulfide Glycolysis Goals Heart Heterozygote Homozygote Human Hypoxia In Vitro Injury Ischemia Knock-out Mass Spectrum Analysis Measures Mediating Metabolic Metabolism Molecular Mus Myocardial NADH NADP NADPH Oxidase Organ Oxidases Oxidation-Reduction Oxidoreductase Oxygen Pentosephosphate Pathway Perfusion Phosphotransferases Preparation Protein Isoforms Reaction Reactive Oxygen Species Reperfusion Therapy Role Small Interfering RNA Stress Testing Time alpha ketoglutarate cancer cell cell injury cofactor cytotoxicity experimental study extracellular glutathione peroxidase heart function in vivo inhibitor inorganic phosphate insight metabolomics mouse model myocardial hypoxia normoxia novel overexpression oxidation pharmacologic preservation response small molecule

项目摘要

Project Summary. Adaptive metabolic responses to hypoxia reflect essential evolutionary survival strategies in all eukaryotes. We recently identified a unique metabolite that increases in cardiovascular (CV) cells in response to hypoxia, L-2-hydroxyglutarate (L2HG). This metabolite is derived from α- ketoglutarate, or 2-oxoglutarate (2OG), a key intermediate in the tricarboxylic acid cycle. Once formed from 2OG and NADH, L2HG has no other metabolic fate except to undergo oxidation back to 2OG by the stereospecific dehydrogenase, L2HG dehydrogenase (L2HGDH), suggesting that it accommodates (‘buffers’) the increase in reducing equivalents accompanying hypoxia. L2HG has two other unique actions: it suppresses glycolysis and, as we show here, it increases pentose phosphate pathway (PPP) activity. The central hypothesis of this proposal is that L2HG suppresses glycolysis and enhances PPP activity in CV cells to eliminate reactive oxygen species (ROS), maintain cell redox potential, and preserve cell function in hypoxia. To address this hypothesis, we will focus on three specific aims. First, we will determine the molecular metabolic mechanisms underlying the effects of L2HG on glycolysis and PPP activity. In particular, we will focus on the unique role of a specific phosphofructokinase-2 isoform, PFKFB4, as a key regulatory determinant of increased flux through the PPP in hypoxia. Second, we will determine the effect of this L2HG-induced increased PPP activity in hypoxia on cellular redox potential and intra- and extracellular ROS elimination. Here, we will focus on PPP-derived NADPH and GSH as key cofactors in NADPH oxidase and glutathione peroxidase activities, respectively, in order to enhance elimination of excess ROS. Third, we will study the effects of L2HG in hypoxia or ischemia on cellular and cardiac function, respectively, using unique cellular and genetic murine models. Taken together, these studies should provide insights into the mechanisms by which L2HG promotes metabolic remodeling to preserve cell and cardiac function in oxygen-limited states.

项目摘要。对缺氧的适应性代谢反应反映了基本的进化生存所有真核生物的策略。我们最近发现了一种独特的代谢物， (CV)细胞对缺氧的反应，L-2-羟基戊二酸（L2 HG）。该代谢产物来源于α- 酮戊二酸或2-酮戊二酸（2 OG），三羧酸循环中的关键中间体。一旦形成从2 OG和NADH，L2 HG没有其他代谢的命运，除了经历氧化回到2 OG的立体特异性脱氢酶，L2 HG脱氢酶（L2 HGDH），这表明它容纳（“缓冲”）伴随缺氧的还原当量的增加。L2 HG还有两个独特的作用：它抑制糖酵解，正如我们在这里显示的，它增加戊糖磷酸途径（PPP）活动该建议的中心假设是L2 HG抑制糖酵解并增强PPP 活性，以消除活性氧（ROS），维持细胞氧化还原电位，并保护细胞缺氧时的功能为了解决这一假设，我们将重点关注三个具体目标。一是确定L2 HG对糖酵解和PPP影响的分子代谢机制活动特别是，我们将集中在一个特定的磷酸果糖激酶-2亚型的独特作用， PFKFB 4，作为缺氧时PPP通量增加的关键调节决定因素。二是确定缺氧时L2 HG诱导的PPP活性增加对细胞氧化还原电位的影响以及细胞内和细胞外ROS消除。在这里，我们将重点关注PPP衍生的NADPH和GSH， NADPH氧化酶和谷胱甘肽过氧化物酶活性的关键辅因子，以增强消除过量的ROS。第三，我们将研究L_2HG在缺氧或缺血状态下对细胞和神经元的影响。心脏功能，分别使用独特的细胞和遗传小鼠模型。综上所述各项研究应该提供深入了解L2 HG促进代谢重塑的机制，在氧限制状态下保护细胞和心脏功能。