The Role of Cardiolipin In The TCA Cycle: Implications For Barth Syndrome

描述（由申请人提供）：心磷脂（CL）是线粒体膜的标志性脂质，是优化线粒体功能、线粒体蛋白输入、线粒体融合、PKC和渗透胁迫信号通路、衰老、液泡/溶酶体功能和神经酰胺合成所必需的。CL存在于所有哺乳动物组织中，但在心脏中含量最多，占磷脂的20%。CL合成紊乱可导致严重危及生命的遗传疾病，称为Barth综合征（BTHS），其特征是扩张性心肌病和心律失常猝死的高发。CL缺乏也与糖尿病性心肌病、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。酵母模型在阐明CL的功能方面起着关键作用，因为它提供了许多目前在其他真核生物系统中无法获得的优势。它是唯一的真核生物，其中零突变体可用于CL合成的每一步。此外，与其他真核生物模型相比，大量的遗传、生化和功能基因组分析可以更容易地应用于酵母。从酵母到人类的疾病相关基因以及复杂细胞过程的功能守恒使得从酵母研究中收集到的知识很可能适用于人类。我们将利用酵母系统和缺CL的哺乳动物细胞来验证新的假设，即缺CL导致线粒体输入铁-硫（Fe）所需蛋白质的缺陷

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.