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

• 批准号: 9238797
• 负责人: Miriam L Greenberg
• 金额: $ 35.65万
• 依托单位: WAYNE STATE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-04-01 至 2019-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9238797
• 关键词: 3-Methylglutaconic aciduria type 2; Aging; Arrhythmia; Biochemical; Bioenergetics; Biogenesis; Biological Assay; Cardiac; Cardiolipins; Cardiomyopathies; Cell physiology; Cells; Ceramides; Citric Acid Cycle; Complex; Data; Defect; Diagnosis; Dilated Cardiomyopathy; Disease; Enzymes; Eukaryota; Exhibits; Genes; Genetic; Genetic Models; Glean; Glutamates; Glutathione; Goals; Heart; Heart failure; Hereditary Disease; Homeostasis; Human; Incidence; Iron; Knowledge; Life; Link; Lipids; Lysosomes; Mammalian Cell; Mediating; Metabolic; Metabolism; Mitochondria; Mitochondrial Proteins; Modeling; Molecular; Molecular Chaperones; Mutation; Myopathy; Organism; Outcome; Pathology; Patients; Phenotype; Phospholipids; Process; Production; Protein Import; Proteins; Publishing; Reperfusion Injury; Research; Role; Saccharomyces cerevisiae; Signal Pathway; Stress; Sudden Death; Sulfur; Supplementation; System; Testing; Time; Tissues; Vacuole; Yeast Model System; Yeasts; base; diabetic cardiomyopathy; enzyme deficiency; exercise intolerance; frataxin; functional genomics; human disease; insight; loss of function; metabolomics; mitochondrial membrane; mitochondrial metabolism; mutant; new therapeutic target; non-alcoholic; non-alcoholic fatty liver; novel; public health relevance; skeletal; yeast genetics

DESCRIPTION (provided by applicant): Cardiolipin (CL), the signature lipid of the mitochondrial membrane, is required for optimal mitochondrial function, as well as mitochondrial protein import, mitochondrial fusion, PKC and osmotic stress signaling pathways, aging, vacuole/lysosome function, and ceramide synthesis. CL is found in all mammalian tissues, but it is most abundant in the heart, where it comprises up to 20% of phospholipids. Perturbation of CL synthesis leads to the severe life- threatening genetic disorder known as Barth syndrome (BTHS), which is characterized by dilated cardiomyopathy and a high incidence of sudden death from arrhythmia. CL deficiency is also implicated in diabetic cardiomyopathy, heart failure, ischemia/reperfusion injury, and nonalcoholic fatty liver disease. Elucidating the mechanisms underlying the involvement of CL in cellular functions would provide insight into these disorders and identify potential new drug targets. The yeast model has been pivotal in elucidating the functions of CL, as it offers numerous advantages not currently available in other eukaryotic systems. It is the only eukaryote in which null mutants are available for every step in CL synthesis. Furthermore, a vast array of genetic, biochemical, and functional genomic analyses can more readily be applied in yeast than in other eukaryotic models. Conservation of function from yeast to humans for disease-associated genes as well as for complex cellular processes makes it likely that knowledge gleaned from yeast studies will be applicable to humans. We will utilize the yeast system as well as CL-deficient mammalian cells to test the novel hypothesis that CL deficiency leads to defective mitochondrial import of proteins required for iron-sulfur (Fe S) biogenesis, resulting in perturbation of the TCA cycle and metabolic deficiencies. Aim 1 will define the mechanism that links CL deficiency to perturbation of Fe-S biogenesis and the TCA cycle in yeast. Aim 2 will identify specific defects in Fe-S biogenesis and the TCA cycle that result from CL deficiency in mammalian cells. This knowledge will facilitate our understanding of highly conserved mechanisms that control mitochondrial metabolism, and will offer the possibility of new directions for the diagnosis and treatment of BTHS and other cardiomyopathies and disorders.

描述（由申请人提供）：心磷脂 (CL) 是线粒体膜的标志性脂质，是最佳线粒体功能以及线粒体蛋白输入、线粒体融合、PKC 和渗透应激信号通路、衰老、液泡/溶酶体功能所必需的和神经酰胺合成。 CL 存在于所有哺乳动物组织中，但在心脏中含量最多，其中磷脂含量高达 20%。 CL合成的干扰会导致严重危及生命的遗传性疾病，称为巴斯综合征（BTHS），其特征是扩张型心肌病和心律失常猝死的高发生率。 CL 缺乏还与糖尿病心肌病、心力衰竭、缺血/再灌注损伤和非酒精性脂肪肝有关。阐明 CL 参与细胞功能的机制将有助于深入了解这些疾病并确定潜在的新药物靶点。酵母模型对于阐明 CL 的功能至关重要，因为它具有目前其他真核系统所不具备的许多优势。它是唯一一种在 CL 合成的每个步骤中都可以使用无效突变体的真核生物。此外，与其他真核模型相比，大量遗传、生化和功能基因组分析可以更容易地应用于酵母。酵母对人类疾病相关基因以及复杂细胞过程的功能保守使得从酵母研究中收集到的知识可能适用于人类。 我们将利用酵母系统以及 CL 缺陷的哺乳动物细胞来测试新的假设，即 CL 缺陷导致铁硫（Fe）所需蛋白质的线粒体输入有缺陷。 S) 生物发生，导致 TCA 循环扰动和代谢缺陷。目标 1 将定义将 CL 缺乏与酵母中 Fe-S 生物合成和 TCA 循环扰动联系起来的机制。目标 2 将识别哺乳动物细胞中因 CL 缺乏而导致的 Fe-S 生物合成和 TCA 循环中的特定缺陷。这些知识将有助于我们理解控制线粒体代谢的高度保守机制，并为 BTHS 和其他心肌病和疾病的诊断和治疗提供新方向的可能性。