Cardiolipin remodeling and its role in mitochondrial function in Barth Syndrome

描述（由申请人提供）：线粒体是ATP产生、代谢物合成和降解、脂质代谢和铁硫簇组装途径的中心。线粒体功能障碍有助于广泛的神经和肌肉疾病，包括心肌病和与x连锁疾病巴斯综合征相关的中性粒细胞减少症，这被归类为一种罕见的疾病。Barth综合征是由基因taafazzin （Taz1）突变引起的，Taz1在线粒体中作为一种假定的心磷脂酰基转移酶起作用。心磷脂是线粒体中发现的一种特殊脂质！心磷脂维持的内膜和缺陷与衰老和细胞凋亡有关。本提案的目标是：(1)通过确定Taz1p在线粒体中的定位和随后的生物发生来研究其功能；(2)以酵母为模型，确定影响心磷脂重塑的小分子效应物。Taz1p生物发生研究将精确定位线粒体内的位置，并为理解小分子效应物调节心磷脂组装的机制提供一个平台。化学文库中的小分子效应物将通过高通量筛选来鉴定，酵母突变体删除了心磷脂组装途径中的蛋白质。将作为模型的生物是出芽酵母酿酒酵母，因为它在遗传和生化上都很容易处理，而且真菌和动物的线粒体生理学的许多方面都很相似。这个研究项目的长期目标是开发工具来研究线粒体脂质在心脏中的生物发生，因为这是一个未被充分研究的途径。从理论上讲，小分子效应物的鉴定应该会导致研究脂质组装和运输途径的新工具的发展，并可能为开发新的治疗方法奠定基础。这些工具随后将应用于哺乳动物系统，如培养的心肌细胞。这一应用对公共卫生有更广泛的影响，因为心脏病影响一般人群。线粒体是心脏产生能量所必需的，心磷脂组装和维持的缺陷可导致心功能障碍。研究心磷脂组装的新工具的发展有可能导致心脏功能障碍治疗方法的发展，并将导致对心脏细胞功能的更好理解。

DESCRIPTION (provided by applicant): The mitochondrion is central for pathways of ATP production, the synthesis and degradation of metabolites, lipid metabolism, and iron-sulfur cluster assembly. Mitochondrial dysfunction contributes to a broad range of neural and muscular diseases including cardiomyopathy and neutropenia associated with the X-linked disease Barth Syndrome, which is categorized as a rare disorder. Barth syndrome is caused by mutations in the gene tafazzin (Taz1) which functions as a putative cardiolipin acyltransferase in the mitochondrion. Cardiolipin is a specific lipid found in the mitochondria! inner membrane and defects in cardiolipin maintenance have been linked to aging and apoptosis. The goals of this proposal are to (1) investigate the function of Taz1p by determining its localization within mitochondria and subsequent biogenesis and (2), using yeast as a model, identify small molecule effectors that affect cardiolipin remodeling. Taz1p biogenesis studies will pinpoint the location within the mitochondrion and provide a platform for understanding the mechanism by which small molecule effectors may modulate cardiolipin assembly. Small molecule effectors from chemical libraries will be identified using a high-throughput screen with yeast mutants deleted for proteins in the cardiolipin assembly pathway. The organism that will serve as a model is the budding yeast Saccharomyces cerevisiae because it is genetically and biochemically tractable and many aspects of mitochondrial physiology are similar between fungi and animals. The long-term goal of this research program is to develop tools for studying mitochondrial lipid biogenesis in the heart because this is an understudied pathway. The identification of small molecule effectors should in theory lead to the development of new tools to investigate lipid assembly and trafficking pathways and potentially lay the groundwork for the development of novel therapeutics. These tools will then be applied to mammalian systems such as cultured cardiomyocytes. This application has a broader impact in public health because cardiac disease affects the general population. The mitochondrion is required for energy production in the heart and defects in cardiolipin assembly and maintenance can lead to cardiac dysfunction. The development of new tools for studying cardiolipin assembly has the potential to lead to the development of therapeutics for cardiac dysfunction and will lead to a better understanding of how the heart cell functions.