Molecular determinants of cardiolipin signalling in mitochondria

我的研究重点是线粒体，这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。线粒体有两层膜，将它们与细胞的其他部分隔开：一层是折叠的内膜，另一层是外膜。重要的调控通路发生在线粒体内，对人类健康和疾病具有关键作用。其中一些途径才刚刚开始被发现，包括我在本提案中选择关注的一条途径。我的目标是解开线粒体的标志性脂质--心磷脂--被用作线粒体降解(有丝分裂)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，它就像是细胞降解线粒体的信号。我们还不知道这一过程是如何发生的，但新的研究表明，NME4蛋白直接通过两层膜转移心磷脂。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信息。这项计划将代表第一次全面的，多学科的分子水平的研究线粒体膜和它们如何协调一致，并让我们新的理解，我们可能如何控制这些途径。这对人类健康和疾病具有重要后果，因为这些过程的错误调节与神经退行性疾病、心肌病和神经性疾病有关。癌症耐药性与这些线粒体质量控制途径之间也存在联系。我的研究计划产生的新认识将被应用于其他相关途径的研究，长期而言，将有望在线粒体质量控制途径中产生潜在的新药靶点。在总体上了解膜蛋白-脂质相互作用方面的进展也将对药物发现计划的推进产生影响。为了最大限度地交流知识并推动该领域的研究向前发展，我的实验室将在整个研究计划过程中与行业合作伙伴建立联系。

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.