Molecular determinants of cardiolipin signalling in mitochondria

点击翻译按钮获取中文摘要

My research focusses on mitochondria, which are important components ('organelles') of our cells, and are responsible for maintaining the stability of our cells. Mitochondria have two membranes, separating them from the rest of the cell; an inner, folded membrane and an outer membrane. Important regulatory pathways occur within mitochondria that have critical roles in human health and disease. Some of these pathways are only beginning to be uncovered, including the one that I choose to focus on within this proposal. I aim to unlock the ways in which the hallmark lipid of mitochondria, cardiolipin, is used as a signal for the mitochondrial degradation ('mitophagy') pathway. We know that during this mitochondrial life/death process cardiolipin is moved from the MIM to the MOM. Once it is there it acts as a signal for the cell to degrade the mitochondrion. We do not yet know how this process is physically able to occur, but new research implicates the protein NME4 in directly transferring cardiolipin across the two membranes. My work combining computer simulations of these molecules with experimental work will provide the first molecular level information on this pathway. This programme will represent the first comprehensive, multidisciplinary molecular level study of both membranes of the mitochondria and how they behave in concert and give us new understanding of how we might control these pathways. This has important consequences in human health and disease, as the misregulation of these processes has been linked to neurodegenerative disorders, cardiomyopathy and neurological disease. There are also links between cancer drug resistance and these mitochondrial quality control pathways.The new understanding generated by my research programme will be applied to study other related pathways and, long-term, will be expected to lead to potential new drug targets in mitochondrial quality control pathways. Advancements in understanding membrane protein-lipid interactions in general will also have implications for the advancement of drug discovery programmes. To maximise the exchange of knowledge and drive research forward in the field, my lab will link up with industrial partners throughout the course of the research programme.