Understanding the structural basis of specificity in mitochondrial lipid transport and its role in drug resistance

线粒体是细胞的能量发生器，在细胞生长和程序性细胞死亡中起着重要作用。当这些细胞过程发生一系列不受欢迎的变化时，诸如癌症之类的疾病就会出现。线粒体的健康需要高度协调的蛋白质和脂肪样分子（称为磷脂）供应，磷脂形成一层包裹蛋白质机器的膜。PRELI/Ups蛋白家族是维持正确磷脂平衡的基础。在这个建议中，我们计划可视化的机制，通过特定的线粒体磷脂可以区分和不同的膜之间分布。通过先进的结构测定方法，如x射线晶体学和核磁共振（NMR），生物分子的形状、柔韧性和相互作用将在溶液中成像。这些结构研究的见解将与细胞方法相结合，以了解PRELI/Ups系统控制脂质运输的特征。这将揭示线粒体调控基本方面的机制，以及可能导致疾病的异常途径。反过来，这将使我们更好地了解身体对癌症药物治疗的反应，以及新治疗方法和监测其可能的效果。

Mitochondria are the power generators for a cell and play important roles in cell growth and as well as programmed cell death. Diseases such as cancer arise when a series of unwelcome changes occur in these cellular processes. Mitochondrial health requires a highly coordinated supply of proteins and fat-like molecules known as phospholipids that form a membrane that encloses the protein machinery. The PRELI/Ups family of proteins is fundamental to maintaining the correct phospholipid balance. In this proposal we plan to visualise the mechanisms by which specific mitochondrial phospholipids can be discriminated and distributed between distinct membranes. By advanced structure determination methods, such as X-ray crystallography and nuclear magnetic resonance (NMR), the shape, flexibility and interaction of biological molecules will be imaged in solution. Insight from these structural studies will be combined with cellular approaches to understand the features that control lipid transport by the PRELI/Ups system. This will shed new light on the mechanisms that underlie fundamental aspects of mitochondrial regulation, and the aberrant pathways that can lead to disease. In turn, this would lead to a better understanding of how the body responds to drug treatments in cancer as well as new treatments and monitoring their likely effectiveness.