Molecular determinants of cardiolipin signalling in mitochondria

线粒体心磷脂信号传导的分子决定因素

• 批准号: MR/T017961/1
• 负责人: Sarah Rouse
• 金额: $ 153.35万
• 依托单位: Imperial College London
• 依托单位国家: 英国
• 项目类别: Fellowship
• 财政年份: 2020
• 资助国家: 英国
• 起止时间: 2020 至 无数据
• 项目状态: 未结题
• 来源: https://gtr.ukri.org/projects?ref=MR%2FT017961%2F1
• 关键词: Molecular; determinants; cardiolipin; signalling; mitochondria

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.

我的研究重点是线粒体，它是细胞的重要组成部分（“细胞器”），负责维持细胞的稳定性。线粒体有两层膜，将它们与细胞的其他部分分开。内折叠膜和外膜。重要的调控途径发生在线粒体内，在人类健康和疾病中发挥着关键作用。其中一些途径才刚刚开始被发现，包括我在本提案中选择重点关注的途径。我的目标是解开线粒体标志性脂质心磷脂作为线粒体降解（“线粒体自噬”）途径信号的方式。我们知道，在线粒体的生命/死亡过程中，心磷脂从 MIM 转移到 MOM。一旦到达那里，它就会充当细胞降解线粒体的信号。我们还不知道这个过程在物理上是如何发生的，但新的研究表明蛋白质 NME4 直接将心磷脂跨过两层膜转移。我将这些分子的计算机模拟与实验工作相结合，将提供有关该途径的第一个分子水平信息。该计划将代表首次对线粒体两膜及其协同行为进行全面、多学科的分子水平研究，并使我们对如何控制这些途径有了新的认识。这对人类健康和疾病产生重要影响，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理解将应用于研究其他相关途径，并且从长远来看，预计将导致线粒体质量的潜在新药物靶点控制途径。一般来说，理解膜蛋白-脂质相互作用的进展也将对药物发现计划的进步产生影响。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工业合作伙伴建立联系。

项目成果

Structure of the cytoplasmic domain of SctV (SsaV) from the Salmonella SPI-2 injectisome and implications for a pH sensing mechanism

沙门氏菌 SPI-2 注射体 SctV (SsaV) 胞质结构域的结构及其对 pH 传感机制的影响

• DOI: 10.3929/ethz-b-000498266
• 发表时间: 2021
• 作者: Matthews-Palmer, Teige R. S.

Measurement of Adenovirus-Based Vector Heterogeneity.

• DOI: 10.1016/j.xphs.2022.12.012
• 发表时间: 2023-04
• 期刊: JOURNAL OF PHARMACEUTICAL SCIENCES
• 影响因子: 3.8
• 作者: Hickey, John M.;Jacob, Shaleem I.;Tait, Andrew S.;Vahid, Fatemeh Dastjerdi;Barritt, Joseph;Rouse, Sarah;Douglas, Alexander;Joshi, Sangeeta B.;Volkin, David B.;Bracewell, Daniel G.
• 通讯作者: Bracewell, Daniel G.

An intermolecular hydrogen bonded network in the PRELID-TRIAP protein family plays a role in lipid sensing.

• DOI: 10.1016/j.bbapap.2022.140867
• 发表时间: 2022-10
• 期刊: Biochimica et biophysica acta. Proteins and proteomics
• 作者: X. Miliara;T. Tatsuta;Akinori Eiyama;T. Langer;S. Rouse;Steve Matthews

Atomistic level characterisation of ssDNA translocation through the E. coli proteins CsgG and CsgF for nanopore sequencing.

• DOI: 10.1016/j.csbj.2021.11.014
• 发表时间: 2021
• 期刊: Computational and structural biotechnology journal
• 影响因子: 6
• 作者: Rattu P;Glencross F;Mader SL;Skylaris CK;Matthews SJ;Rouse SL;Khalid S
• 通讯作者: Khalid S

Structure of the cytoplasmic domain of SctV (SsaV) from the Salmonella SPI-2 injectisome and implications for a pH sensing mechanism.

• DOI: 10.1016/j.jsb.2021.107729
• 发表时间: 2021-06
• 期刊: Journal of structural biology
• 影响因子: 3
• 作者: Matthews-Palmer TRS;Gonzalez-Rodriguez N;Calcraft T;Lagercrantz S;Zachs T;Yu XJ;Grabe GJ;Holden DW;Nans A;Rosenthal PB;Rouse SL;Beeby M
• 通讯作者: Beeby M