Cardiolipin remodeling--role in mitochondrial function

描述(由申请人提供)：线粒体是ATP生产、代谢产物的合成和降解、脂肪代谢和铁-硫簇组装的中心。线粒体功能障碍导致一系列神经和肌肉疾病，包括心肌病和与X连锁疾病Barth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Tafazzin(Taz1)基因突变引起的，Tafazzin基因在线粒体中起着假定的心磷脂酰基转移酶的作用。心磷脂是线粒体中发现的一种特殊的脂类！心磷脂维持中的内膜和缺陷与衰老和细胞凋亡有关。这项建议的目的是(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Taz1p的功能，以及(2)以酵母为模型，识别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，并为了解小分子效应器调节心磷脂组装的机制提供平台。来自化学文库的小分子效应器将使用高通量筛选，其中删除了心磷脂组装途径中蛋白质的酵母突变体。将作为模式的生物是萌芽酵母酿酒酵母，因为它在遗传和生物化学上都很容易驯化，而且真菌和动物在线粒体生理的许多方面都很相似。这项研究计划的长期目标是开发工具来研究心脏中线粒体脂质的生物发生，因为这是一个未被充分研究的途径。从理论上讲，小分子效应物的识别应该会导致开发新的工具来研究脂质的组装和运输途径，并可能为开发新的治疗方法奠定基础。然后，这些工具将被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，因为心脏病影响普通人群。线粒体是心脏产生能量所必需的，心磷脂组装和维护的缺陷可能导致心脏功能障碍。研究心磷脂组装的新工具的开发有可能导致心功能障碍治疗的发展，并将导致更好地了解心脏细胞的功能。

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.