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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：
10533827
负责人：
Miriam L Greenberg
金额：
$ 37.15万
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 2024-12-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10533827
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 Ischemia 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 clinical phenotype cofactor diabetic cardiomyopathy electron energy experimental study frataxin metabolomics mitochondrial cardiomyopathies 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.

项目摘要心磷脂（CL）是线粒体膜的标志性脂质，对于最佳的细胞生长至关重要。线粒体功能CL的重要性通过以下事实强调：CL的扰动由于CL重塑酶tafazzin（Taz）的突变导致的代谢导致生命- Barth综合征（BTHS）虽然扩张型的临床表型心肌病和骨骼肌病指向线粒体生物能量缺陷，还具有广泛的代谢失调的特征，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起着重要的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和BTHS中的病理联系起来的机制是未知的。我们正在研究的作用，CL代谢使用两个强大的模型。酵母CL 突变体，crd 1D，我们以前产生的是一个完善的CL缺陷模型。更最近，我们在小鼠成肌细胞C2 C12细胞系中构建了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，贡献了一种新的疾病模型。通过实现这两种模型，我们确定CL 调节聚集在TCA循环上的两个途径-乙酰辅酶A合成和Fe-S 生物起源基于这些发现，将使用遗传学、生物化学和代谢组学方法为了检验中心假设，即CL是TCA循环的最佳活性所必需的，其在调节乙酰辅酶A合成和Fe-S辅因子生物合成中的双重作用。目标1将定义CL通过增加乙酰辅酶A的活性来调节乙酰辅酶A合成的机制。丙酮酸脱氢酶目的2将描述挽救TCA循环的回补机制缺陷目的3提出确定CL在yfh 1/共济失调蛋白成熟中的作用，这是一个重要的 Fe-S机械的组成部分。 TCA循环是碳代谢的重要代谢途径。的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中的作用周期阐明这种调节作用的机制将建立一种新的范式用于三醋酸循环控制。这些结果可能为BTHS和其他疾病提供潜在的新治疗方法。线粒体心肌病

项目成果

期刊论文数量（19）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Get1p and Get2p are required for maintenance of mitochondrial morphology and normal cardiolipin levels.

Get1p 和 Get2p 是维持线粒体形态和正常心磷脂水平所必需的。

DOI：
10.1093/femsyr/fow019
发表时间：
2016
期刊：
FEMS yeast research
影响因子：
3.2
作者：
Joshi,AmitS;Fei,Naomi;Greenberg,MiriamL
通讯作者：
Greenberg,MiriamL

Loss of Cardiolipin Leads to Perturbation of Acetyl-CoA Synthesis.

心磷脂的损失会导致乙酰辅酶A合成受到干扰。

DOI：
10.1074/jbc.m116.753624
发表时间：
2017
期刊：
The Journal of biological chemistry
影响因子：
0
作者：
Raja,Vaishnavi;Joshi,AmitS;Li,Guiling;Maddipati,KrishnaRao;Greenberg,MiriamL
通讯作者：
Greenberg,MiriamL

Isoforms of the transcriptional cofactor SIN3 differentially regulate genes necessary for energy metabolism and cell survival.

DOI：
10.1016/j.bbamcr.2022.119322
发表时间：
2022-10
期刊：
Biochimica et biophysica acta. Molecular cell research
影响因子：
0
作者：
通讯作者：

Cardiolipin-deficient cells depend on anaplerotic pathways to ameliorate defective TCA cycle function.

心磷脂缺陷细胞依赖补补途径来改善有缺陷的 TCA 循环功能。

DOI：
10.1016/j.bbalip.2019.02.001
发表时间：
2019
期刊：
Biochimica et biophysica acta. Molecular and cell biology of lipids
影响因子：
0
作者：
Raja,Vaishnavi;Salsaa,Michael;Joshi,AmitS;Li,Yiran;vanRoermund,CarloWT;Saadat,Nadia;Lazcano,Pablo;Schmidtke,Michael;Hüttemann,Maik;Gupta,SmitiV;Wanders,RonaldJA;Greenberg,MiriamL
通讯作者：
Greenberg,MiriamL

The Role of Cardiolipin in Cardiovascular Health.