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

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间，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，保持细胞的存活和健康。大脑中，神经细胞（神经元）独特的特性和功能对细胞器提出了额外的要求，因此，高效的细胞器间团队合作尤为重要。事实上，功能失调的细胞器合作与许多神经和神经退行性疾病有关，这是英国及其他地区的主要社会经济负担。网络中的细胞器相互“交谈”的一种方式是共享信息，物理接触点上的信号和资源被称为“膜接触点”。细胞膜接触部位细胞器之间的协调合作对细胞功能和存活至关重要。尽管如此，大多数细胞器在接触部位是如何交流的，以及为了什么目的，仍然不清楚。因为我们还不了解这一点，所以我们不知道在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信的机制，并揭示从这种合作中受益的细胞过程。这些知识将极大地促进我们对细胞生物学的理解，并为细胞器通信的有害变化如何导致疾病提供新的见解，并可能有一天成为新的治疗目标。鉴于人口老龄化导致脑功能下降的巨大社会成本，我的研究将集中在神经细胞上，我的目标是解释：神经细胞内细胞器间通信的机制和功能表明，细胞器通信错误导致疾病，细胞器通信如何可以治疗针对性地改善神经细胞健康。我将利用我现有的专业知识集中在两个细胞器上，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“发电站”。两者都是细胞存活所必需的，在健康的脑功能中起着至关重要的作用，任何一种细胞器的遗传缺陷都会导致毁灭性的疾病，这些疾病通常与神经功能衰退有关。过氧化物酶体和线粒体紧密相连，因为它们协同作用：1)处理细胞内的脂肪分子；2)控制可能有害的“自由基”分子的水平，这些分子会破坏细胞成分。过氧化物酶体-线粒体的交流在大脑中显得尤为重要，因为神经细胞比其他类型的细胞含有更多的过氧化物酶体-线粒体接触。尽管如此，过氧化物酶体和线粒体之间的膜接触部位，它们在神经细胞功能中的作用，以及它们对疾病的贡献，都知之甚少。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来解决三个特定目标：线粒体和过氧化物酶体如何物理相互作用？神经细胞中过氧化物酶体-线粒体通讯的功能是什么？调节过氧化物酶体-线粒体通讯能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信的理解，并为未来对其他关键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，这些知识将最终推动治疗方法的发展，改善这些过程失调的各种疾病的神经细胞健康。

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.