Cardiolipin remodeling--role in mitochondrial function

心磷脂重塑——在线粒体功能中的作用

• 批准号: 7144272
• 负责人: Carla M Koehler
• 金额: $ 22.39万
• 依托单位: UNIVERSITY OF CALIFORNIA LOS ANGELES
• 依托单位国家: 美国
• 财政年份: 2006
• 资助国家: 美国
• 起止时间: 2006-05-01 至 2008-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7144272
• 关键词: Saccharomyces cerevisiae; acyltransferase; cardiolipins; cardiovascular pharmacology; congenital cardiovascular disorder; fungal genetics; gene mutation; genetic disorder; high throughput technology; hypertrophic myocardiopathy; lipid metabolism; membrane proteins; mitochondrial membrane; orphan disease /drug; protein biosynthesis; protein localization; small molecule; yeast two hybrid system; zebrafish

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.

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核心。线粒体功能障碍会导致多种神经和肌肉疾病，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，该综合征被归类为一种罕见疾病。巴斯综合征是由基因 tafazzin (Taz1) 突变引起的，该基因在线粒体中充当假定的心磷脂酰基转移酶。心磷脂是线粒体中发现的一种特殊脂质！内膜和心磷脂维持缺陷与衰老和细胞凋亡有关。该提案的目标是 (1) 通过确定 Taz1p 在线粒体内的定位和随后的生物发生来研究 Taz1p 的功能，以及 (2) 使用酵母作为模型，识别影响心磷脂重塑的小分子效应子。 Taz1p 生物发生研究将查明线粒体内的位置，并为了解小分子效应器调节心磷脂组装的机制提供一个平台。将使用高通量筛选来鉴定化学文库中的小分子效应物，其中删除了心磷脂组装途径中蛋白质的酵母突变体。用作模型的生物体是芽殖酵母酿酒酵母，因为它在遗传和生化上易于处理，并且真菌和动物之间线粒体生理学的许多方面相似。该研究计划的长期目标是开发用于研究心脏线粒体脂质生物发生的工具，因为这是一条尚未得到充分研究的途径。理论上，小分子效应物的识别应该会导致新工具的开发来研究脂质组装和运输途径，并可能为新疗法的开发奠定基础。这些工具随后将应用于哺乳动物系统，例如培养的心肌细胞。该应用对公共健康具有更广泛的影响，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促进心脏功能障碍疗法的开发，并将导致更好地了解心脏细胞的功能。