THE ROLE OF CARDIOLIPIN IN THE TCA CYCLE: IMPLICATIONS FOR BARTH SYNDROME

心磷脂在 TCA 循环中的作用：对巴斯综合征的影响

基本信息

批准号：
10322118
负责人：
Miriam L Greenberg
金额：
$ 37.2万
依托单位：
WAYNE STATE UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2014
资助国家：
美国
起止时间：
2014-04-01 至 2023-12-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10322118
关键词：
3-Methylglutaconic aciduria type 2 Acetyl Coenzyme A Aconitate Hydratase Amino Acids Arrhythmia Binding Biochemical Bioenergetics Biogenesis Carbon Cardiolipins Cardiomyopathies Catalytic Domain Cell Line Cells Characteristics Citric Acid Cycle Defect Dilated Cardiomyopathy Disease Disease model Energy Metabolism Enzymes Exhibits Genetic Genetic Diseases Glucose Heart failure Holoenzymes Iron Knock-out Left Life Link Lipids Metabolic Metabolic Pathway Metabolism Mitochondria Mitochondrial Myopathies Modeling Molecular Mus Mutation Myoblasts Myopathy Nucleotides Oxidative Phosphorylation Pathogenesis Pathologic Pathology Pathway interactions Phenotype Phospholipids Phosphorylation Play Production Protein Dephosphorylation Pyruvate Reaction Regulation Reperfusion Injury Reporting Role Route Succinate Dehydrogenase Sulfur Testing Yeast Model System Yeasts base clinical phenotype cofactor diabetic cardiomyopathy electron energy experimental study frataxin metabolomics mitochondrial membrane mutant non-alcoholic fatty liver disease novel public health relevance pyruvate dehydrogenase skeletal

项目摘要

Project Summary Cardiolipin (CL), the signature lipid of the mitochondrial membrane, is crucial for optimal mitochondrial function. The importance of CL is underscored by the fact that perturbation of CL metabolism due to mutation of the CL remodeling enzyme tafazzin (Taz) leads to the life- threatening genetic disorder, Barth syndrome (BTHS). While the clinical phenotypes of dilated cardiomyopathy and skeletal myopathy point to mitochondrial bioenergetic defects, the disorder is also characterized by broad metabolic dysregulation, including abnormal levels of amino acids and TCA cycle-associated metabolites. These studies suggest that CL plays an important role not only in oxidative phosphorylation but also in intermediary metabolism. The molecular mechanisms linking CL deficiency to these metabolic changes and to the pathologies in BTHS are unknown. We are investigating the role of CL in metabolism using two powerful models. The yeast CL mutant, crd1D, which we generated previously is a well-established model of CL deficiency. More recently, we constructed a Taz knockout mutant, TAZ-KO, in the mouse myoblast C2C12 cell line. TAZ-KO cells exhibit the characteristic biochemical and mitochondrial phenotypes of BTHS and contribute a new model of the disorder. Implementing both models, we have determined that CL regulates two pathways that converge on the TCA cycle - acetyl-CoA synthesis and Fe-S biogenesis. Based on these findings, will use genetic, biochemical, and metabolomic approaches to test the central hypothesis that CL is required for optimal activity of the TCA cycle as a result of its dual role in regulating synthesis of acetyl-CoA and biogenesis of Fe-S cofactors. Aim 1 will define the mechanism whereby CL regulates acetyl-CoA synthesis by increasing the activity of pyruvate dehydrogenase. Aim 2 will characterize anaplerotic mechanisms that rescue TCA cycle deficiencies. Aim 3 proposes to define the role of CL in maturation of yfh1/frataxin, an essential component of the Fe-S machinery. The TCA cycle is a fundamentally important metabolic pathway of carbon metabolism. The current study is driven by a novel hypothesis that identifies a role for CL in regulating the TCA cycle. Elucidating the mechanisms underlying this regulatory role will establish a new paradigm for TCA cycle control. The results may suggest potential new treatments for BTHS and other mitochondrial cardiomyopathies.

项目摘要 Cardiolipin（Cl）是线粒体膜的签名脂质，对于最佳线粒体功能。 CL的扰动强调了Cl的重要性由于CL重塑酶Tafazzin（TAZ）的突变引起的代谢导致生命 - 威胁遗传疾病，巴特综合征（BTHS）。而扩张的临床表型心肌病和骨骼肌病指向线粒体生物能缺陷，该疾病还具有广泛的代谢失调，包括异常水平的氨基酸和与TCA周期相关的代谢产物。这些研究表明，CL起着重要作用不仅在氧化磷酸化中，而且在中间代谢中。分子将CL缺乏症与这些代谢变化和BTH中的病理联系起来的机制是未知的。我们正在使用两个强大的模型研究CL在代谢中的作用。酵母Cl 我们先前生成的突变体CRD1D是CL缺乏症的公认模型。更多的最近，我们在小鼠成肌细胞C2C12细胞系中构建了一个TAZ敲除突变体TAZ-KO。 TAZ-KO细胞表现出BTHS的特征性生化和线粒体表型为该疾病的新模型做出贡献。实施这两个模型，我们已经确定CL 调节在TCA循环-Acetyl-COA合成和Fe-S上收敛的两个途径生物发生。基于这些发现，将使用遗传，生化和代谢组方法为了测试中心假设，即CL是TCA循环最佳活性所必需的其在调节乙酰辅酶A的合成和Fe-S辅因子的生物发生中的双重作用。目标1意志定义CL通过增加的活性来调节乙酰辅酶A的合成的机制丙酮酸脱氢酶。 AIM 2将表征拯救TCA周期的杂质性机制缺陷。 AIM 3建议定义CL在YFH1/Frataxin成熟中的作用，这是必不可少的 Fe-S机械的组成部分。 TCA周期是碳代谢的根本重要代谢途径。这当前的研究是由一个新的假设驱动的，该假设鉴定了CL在调节TCA中的作用循环。阐明这种调节作用的机制将建立新的范式用于TCA周期控制。结果可能表明对BTH和其他的潜在新疗法线粒体心肌病。