Molecular determinants of cardiolipin signalling in mitochondria

我的研究重点是线粒体，它是我们细胞的重要组成部分（“细胞器”），负责维持我们细胞的稳定性。线粒体有两层膜，将它们与细胞的其他部分隔开；一种内折叠膜和一种外膜。重要的调控途径发生在线粒体内，在人类健康和疾病中起着关键作用。其中一些途径才刚刚开始被发现，包括我选择在本提案中重点关注的途径。我的目标是解开线粒体的标志性脂质，心磷脂，作为线粒体降解（“线粒体自噬”）途径的信号的方式。我们知道，在线粒体的生死过程中，心磷脂从MIM转移到MOM。一旦它在那里，它就会作为细胞降解线粒体的信号。我们还不知道这个过程是如何在物理上发生的，但是新的研究表明NME4蛋白直接在两层膜上转移心磷脂。我的工作将这些分子的计算机模拟与实验工作相结合，将提供关于这一途径的第一个分子水平的信息。这个项目将代表着第一个全面的、多学科的线粒体膜分子水平的研究，以及它们是如何协同工作的，并为我们如何控制这些途径提供了新的认识。这对人类健康和疾病有重要影响，因为这些过程的失调与神经退行性疾病、心肌病和神经系统疾病有关。癌症耐药性和线粒体质量控制途径之间也存在联系。我的研究项目产生的新认识将应用于研究其他相关途径，长期来看，有望在线粒体质量控制途径中找到潜在的新药物靶点。了解膜蛋白-脂质相互作用的进展也将对药物发现计划的进展产生影响。为了最大限度地交流知识并推动该领域的研究，我的实验室将在整个研究计划的过程中与工业伙伴建立联系。

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.