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

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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.