Organelle teamwork: understanding how peroxisomes and mitochondria communicate in neuronal cell function

细胞器团队合作：了解过氧化物酶体和线粒体在神经细胞功能中如何沟通

• 批准号: BB/Z514767/1
• 负责人: Ruth Carmichael
• 金额: $ 53.53万
• 依托单位: UNIVERSITY OF EXETER
• 依托单位国家: 英国
• 项目类别: Fellowship
• 财政年份: 2024
• 资助国家: 英国
• 起止时间: 2024 至 无数据
• 项目状态: 未结题
• 来源: https://gtr.ukri.org/projects?ref=BB%2FZ514767%2F1
• 关键词: Organelle; teamwork; understanding; how; peroxisomes

Our bodies are made up of trillions of cells, each of which contains an array of specialised compartments, known as organelles. Each type of organelle has its own important job to do, but must also cooperate with other types of organelles to form an integrated network that keeps cells alive and healthy. Efficient inter-organelle teamwork is particularly critical in the brain, where the unique properties and functions of nerve cells (neurons) place extra demands on organelles. Indeed, dysfunctional organelle cooperation has been implicated in many neurological and neurodegenerative diseases, which are a major socio-economic burden in the UK and beyond.One way organelles within a network 'talk' to each other is by sharing information, signals and resources at points of physical contact called 'membrane contact sites'. Orchestrated cooperation between organelles at membrane contact sites is vital for cell function and survival. Despite this, how most organelles communicate at contact sites, and for what purposes, is still unclear. Because we do not yet understand this, we do not know which processes are compromised during disease, or how to correct these using medical treatment. This research project seeks to identify and characterise the machinery that mediates organelle communication, and reveal the cellular processes that benefit from this cooperation. This knowledge will significantly advance our understanding of cell biology and provide new insights into how detrimental changes in organelle communication cause disease, and might one day be targeted for new treatments.Given the immense social cost of declining brain function in ageing populations, my research will focus on nerve cells, where my aim is to explain:the mechanisms and functions of inter-organelle communication within nerve cellshow faulty organelle communication leads to diseasehow organelle communication can be therapeutically targeted to improve nerve cell healthI will use my existing expertise to concentrate on two organelles, namely peroxisomes and mitochondria. Peroxisomes act as factories within the cell, making and breaking-down important cellular molecules, while mitochondria are 'power-houses' that generate most of the cell's energy. Both are essential for cell survival and play crucial roles in healthy brain function, with inherited defects in either organelle causing devastating diseases that are frequently associated with neurological decline.Peroxisomes and mitochondria are closely linked because they act in concert to 1) process fat molecules within the cell and 2) control levels of potentially harmful 'free-radical' molecules that can damage cellular components. Peroxisome-mitochondria communication appears to be particularly important in the brain since nerve cells contain more peroxisome-mitochondria contacts than other cell types. Despite this, membrane contact sites between peroxisomes and mitochondria, their roles in nerve cell function, and their contribution to disease, are poorly understood.I will use my expertise in a variety of cutting-edge cell biology, microscopy and large-scale screening techniques to address three specific objectives:How do mitochondria and peroxisomes physically interact?What is the function of peroxisome-mitochondria communication in nerve cells?Can modulating peroxisome-mitochondria communication improve nerve cell health?The insights generated will fundamentally advance our understanding of organelle communication in health and disease, and inform future studies on other crucial organelle interactions. Furthermore, in conjunction with my collaborators in the pharmaceutical industry, this knowledge will ultimately drive the development of treatments that improve nerve cell health in a variety of diseases where these processes are dysregulated.

我们的身体由数万亿个细胞组成，每个细胞都包含一系列专门的隔室，称为细胞器。每种类型的细胞器都有自己重要的工作要做，但也必须与其他类型的细胞器合作，形成一个完整的网络，以保持细胞的活力和健康。高效的细胞器间团队合作在大脑中尤其重要，因为神经细胞（神经元）的独特特性和功能对细胞器提出了额外的要求。事实上，功能失调的细胞器合作与许多神经系统和神经退行性疾病有关，这些疾病是英国及其他地区的主要社会经济负担。网络内的细胞器相互“交谈”的一种方式是通过共享信息、信号和资源物理接触点称为“膜接触点”。膜接触位点细胞器之间精心策划的合作对于细胞功能和生存至关重要。尽管如此，大多数细胞器如何在接触位点进行通信以及出于什么目的仍不清楚。因为我们还不了解这一点，所以我们不知道疾病期间哪些过程受到损害，也不知道如何通过药物治疗来纠正这些过程。该研究项目旨在识别和表征介导细胞器通讯的机制，并揭示从这种合作中受益的细胞过程。这些知识将极大地增进我们对细胞生物学的理解，并为细胞器通讯的有害变化如何导致疾病提供新的见解，并且有一天可能成为新治疗的目标。考虑到老年人脑功能衰退的巨大社会成本，我的研究将重点关注神经细胞，我的目的是解释：神经细胞内细胞器间通讯的机制和功能显示错误的细胞器通讯导致疾病如何通过治疗靶向细胞器通讯来改善神经细胞健康我将利用我现有的专业知识专注于两个细胞器，即过氧化物酶体和线粒体。过氧化物酶体充当细胞内的工厂，制造和分解重要的细胞分子，而线粒体是产生细胞大部分能量的“发电厂”。两者对于细胞生存至关重要，并且在健康的大脑功能中发挥着至关重要的作用，任一细胞器的遗传缺陷都会导致通常与神经功能衰退相关的毁灭性疾病。过氧化物酶体和线粒体密切相关，因为它们协同作用：1) 处理体内的脂肪分子2) 控制可能损害细胞成分的潜在有害“自由基”分子的水平。过氧化物酶体-线粒体通讯似乎在大脑中特别重要，因为神经细胞比其他细胞类型含有更多的过氧化物酶体-线粒体接触。尽管如此，人们对过氧化物酶体和线粒体之间的膜接触位点、它们在神经细胞功能中的作用以及它们对疾病的贡献知之甚少。我将利用我在各种尖端细胞生物学、显微镜和大规模筛选技术方面的专业知识解决三个具体目标：线粒体和过氧化物酶体如何物理相互作用？过氧化物酶体-线粒体通讯在神经细胞中的功能是什么？调节过氧化物酶体-线粒体通讯可以改善神经细胞健康吗？所产生的见解将从根本上推进我们对健康和疾病中细胞器通讯的理解，并为未来其他重要细胞器相互作用的研究提供信息。此外，与我在制药行业的合作者一起，这些知识最终将推动治疗方法的开发，以改善这些过程失调的各种疾病的神经细胞健康。