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：
10077881
负责人：
Miriam L Greenberg
金额：
$ 37.25万
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/10077881
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.

项目概要心磷脂 (CL) 是线粒体膜的标志性脂质，对于最佳状态至关重要线粒体功能。 CL 的扰动这一事实强调了 CL 的重要性由于 CL 重塑酶 tafazzin (Taz) 突变导致的代谢导致生命- 威胁性遗传疾病，巴斯综合征（BTHS）。虽然扩张的临床表型心肌病和骨骼肌病表明线粒体生物能缺陷，这种疾病其特征还在于广泛的代谢失调，包括氨基酸水平异常和 TCA 循环相关代谢物。这些研究表明 CL 发挥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 缺乏与这些代谢变化以及 BTHS 病理联系起来的机制未知。我们正在使用两个强大的模型研究 CL 在新陈代谢中的作用。酵母CL 我们之前生成的突变体 crd1D 是一个成熟的 CL 缺陷模型。更多的最近，我们在小鼠成肌细胞C2C12细胞系中构建了Taz敲除突变体TAZ-KO。 TAZ-KO 细胞表现出 BTHS 和 BTHS 的特征性生化和线粒体表型贡献了一种新的疾病模型。实现这两个模型，我们确定 CL 调节 TCA 循环的两条途径 - 乙酰辅酶 A 合成和 Fe-S 生物发生。基于这些发现，将使用遗传、生化和代谢组学方法检验中心假设，即 CL 是 TCA 循环最佳活动所必需的其在调节乙酰辅酶A合成和Fe-S辅因子生物发生中的双重作用。目标1将定义 CL 通过增加乙酰辅酶 A 活性来调节乙酰辅酶 A 合成的机制丙酮酸脱氢酶。目标 2 将描述拯救 TCA 循环的回补机制的不足。目标 3 建议定义 CL 在 yfh1/frataxin 成熟中的作用，yfh1/frataxin 是一种重要的 Fe-S 机械的组成部分。 TCA循环是碳代谢的一个极其重要的代谢途径。这目前的研究是由一个新的假设驱动的，该假设确定了 CL 在调节 TCA 中的作用循环。阐明这种监管作用背后的机制将建立一个新的范式用于TCA循环控制。结果可能为 BTHS 和其他疾病提供潜在的新疗法线粒体心肌病。