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.

我的研究集中在线粒体上，线粒体是我们细胞的重要组成部分（“细胞器”），并负责维持细胞的稳定性。线粒体有两个膜，将它们与细胞的其余部分分开。内部折叠的膜和外膜。在线粒体内发生重要的调节途径在人类健康和疾病中具有关键作用。这些途径中的一些才刚刚开始被发现，包括我选择在此提案中关注的途径。我的目的是解锁线粒体的标志性脂质，Cardiolipin，用作线粒体降解（'Mitophagy）途径的信号。我们知道，在这种线粒体生命/死亡过程中，心磷脂从MIM转移到了妈妈。一旦存在，它就会充当细胞降解线粒体的信号。我们尚不知道该过程是如何在物理上发生的，但是新的研究暗示了蛋白质NME4在将心脂蛋白直接转移到两个膜上。我将这些分子与实验工作结合的计算机模拟结合在一起的工作将提供有关该途径的第一个分子水平信息。该程序将代表两种膜的首次全面，多学科的分子水平研究，以及它们如何共同行事，并使我们对如何控制这些途径有了新的了解。这在人类健康和疾病中产生了重要的后果，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用于研究其他相关途径，并且长期有望导致线粒体质量控制途径中潜在的新药物靶标。一般而言，了解膜蛋白脂质相互作用的进步也将对药物发现计划的发展产生影响。为了最大程度地提高知识的交流并推动了该领域的研究，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

Structural and regulatory insights into the glideosome-associated connector from Toxoplasma gondii.

• DOI: 10.7554/elife.86049
• 发表时间: 2023-04-04
• 期刊: eLife
• 影响因子: 7.7
• 作者: Kumar A;Vadas O;Dos Santos Pacheco N;Zhang X;Chao K;Darvill N;Rasmussen HØ;Xu Y;Lin GM;Stylianou FA;Pedersen JS;Rouse SL;Morgan ML;Soldati-Favre D;Matthews S
• 通讯作者: Matthews S