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

我们的身体由数以万亿计的细胞组成，每个细胞都包含一系列被称为细胞器的特殊隔间。每种类型的细胞器都有自己的重要工作要做，但也必须与其他类型的细胞器合作，形成一个完整的网络，以保持细胞的生命和健康。在大脑中，有效的细胞器间团队合作尤其关键，因为神经细胞(神经元)的独特属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和神经退行性疾病有关，这些疾病在英国和国外都是一个主要的社会经济负担。一个网络中的细胞器相互对话的一种方式是通过在物理接触点共享信息、信号和资源，称为膜接触点。膜接触部位的细胞器之间的协调合作对细胞的功能和生存至关重要。尽管如此，大多数细胞器如何在接触部位进行交流，以及为了什么目的，仍然不清楚。由于我们还不了解这一点，我们不知道哪些过程在疾病期间受到损害，也不知道如何使用医疗手段纠正这些过程。这项研究项目试图确定和描述调节细胞器交流的机制，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，并为细胞器通信中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。鉴于老龄化人口大脑功能下降的巨大社会成本，我的研究将集中在神经细胞，我的目的是解释：神经细胞内细胞器间通信的机制和功能表明，细胞器通信故障会导致疾病，如何从治疗的角度针对细胞器通信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，而线粒体则是产生细胞大部分能量的“动力库”。两者都是细胞生存的关键，在健康的大脑功能中发挥着关键作用，两个细胞器中的遗传缺陷都会导致毁灭性的疾病，这些疾病往往与神经系统的衰退有关。过氧化物体和线粒体密切相关，因为它们协同作用，1)处理细胞内的脂肪分子，2)控制潜在有害的自由基分子的水平，这些分子可能会破坏细胞成分。由于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，因此在大脑中过氧化酶体-线粒体通讯似乎特别重要。尽管如此，过氧化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，还没有得到很好的理解。我将利用我在各种尖端细胞生物学、显微镜和大规模筛查技术方面的专业知识来解决三个具体目标：线粒体和过氧化物体如何物理上相互作用？过氧化酶体-线粒体通讯在神经细胞中的作用是什么？调节过氧化酶体-线粒体通讯能否改善神经细胞的健康？所产生的见解将从根本上促进我们对细胞器通讯在健康和疾病中的理解，并为未来其他关键细胞器相互作用的研究提供参考。此外，与我在制药行业的合作伙伴一起，这一知识最终将推动治疗方法的开发，以改善这些过程失控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.