A complete model of oxygen consumption by mitochondrial cytochrome c oxidase

我们的身体从脂肪、蛋白质和碳水化合物的可控燃烧（氧化）中获得大部分可用能量。因此，向器官（心脏、大脑等）输送氧气对健康、生长和发育至关重要。氧气输送或消耗的问题是造成许多疾病过程的不良影响的原因，例如中风后的脑损伤，心脏病发作等。人体中几乎所有（约95%）的氧气都被一个存在于所有细胞中的小器官（细胞器）消耗掉了。这被称为线粒体。在线粒体内部，一种叫做细胞色素c氧化酶（CCO）的蛋白质催化剂（酶）消耗了所有的氧气；氧气被转化为水，在线粒体上产生电压，最终被用来制造一种叫做三磷酸腺苷（ATP）的分子；ATP是所有细胞的通用能量货币，驱动肌肉运动、大脑信号、生长、发育、组织修复等。CCO含有许多有色的铁和铜中心，这使得在完整的人类中检测到CCO成为可能，例如在“思考”时的大脑中或在运动时的肌肉中。这项拨款的目的是研究CCO在体内是如何被控制的，特别是为了提高我们对这些信号的理解，我们可以无创地测量。这是一个复杂的问题，我们将通过体外（试管）实验和数学建模的结合来解决。它利用了生物学、物理学、数学、生物化学和细胞生物学的专业知识。我们将首先优化试管中不同颜色信号的测量。然后我们将研究这些信号在体外是如何被控制的。由此，我们的最终目标是开发一个动态的数学模型，以演示如何在整个身体（体内）控制它。我们将在这个项目中专注于一个器官（大脑），有两个原因；大脑的生存严重依赖于氧气，有很多关于大脑氧气消耗和输送到大脑的体内数据。我们理解这个复杂系统的一个关键部分是理解它在一系列层面上是如何工作的。因此，我们将开发CCO自身、线粒体内的CCO和整个大脑中的CCO如何消耗氧气的模型。我们将在组织的每个级别使用适当的实验来定义和测试模型的工作方式。特别是，我们将要求来自世界各地的同事根据他们的数据和他们自己的理论，批判性地分析我们的模型。最终的目标将是理解这个复杂的生物系统是如何在“还原论”的分子和更“整体”的器官水平上工作的。除了对其本身感兴趣外，对该系统的改进描述可能对医疗保健和工业（特别是对制造测量体内氧气和能量相关参数的机器的人）具有重要意义。

Our bodies derive most of their useable energy from the controlled burning (oxidation) of fats, proteins and carbohydrates by the gas, oxygen. Oxygen delivery to organs (heart, brain etc.) is therefore vital for health, growth and development. Problems with oxygen delivery or consumption are responsible for the bad effects of many disease processes e.g. brain damage after a stroke, heart attacks etc. Nearly all (>95%) of the oxygen in the body is consumed by a small organ (organelle) found inside all cells. This is called the mitochondrion. Inside the mitochondrion one protein catalyst (enzyme) called cytochrome c oxidase (CCO) consumes all the oxygen; the oxygen is converted into water, generating a voltage across the mitochondrion that eventually is used to make a molecule called adenosine triphosphate (ATP); ATP is the universal energy currency of all cells and drives muscle movement, brain signalling, growth, development, tissue repair etc. CCO contains a number of coloured iron and copper centres that, uniquely, make it possible to detect it in intact humans e.g. in the brain during 'thinking' or in the muscle during exercise. The purpose of this grant is to study how CCO is controlled in the body, in particular in order to improve our understanding of these signals that we can measure non-invasively. This is a complex problem that we will address by using a combination of in vitro (test tube) experiments and mathematical modelling. It utilises the expertises of biology, physics, mathematics, biochemistry and cell biology. We will first optimise the measurement of the different coloured signals in the test tube. We will then look at how these signals are controlled in vitro. From this our ultimate aim is to develop a dynamic mathematical model that will demonstrate how it might be controlled in the whole body (in vivo). We will focus in this project on one organ (the brain) for two reasons; the brain is critically dependent on oxygen for survival and there is a lot of in vivo data about its oxygen consumption and delivery to the brain. A key part of our understanding of this complex system is to understand how it works at a range of levels. We will therefore develop models of how oxygen is consumed in CCO on its own, CCO within the mitochondrion and CCO in the whole brain. We will use appropriate experiments at each level of organisation to define and test how the model works. In particular we will ask colleagues from around the world to analyse our model critically, both with respect to their data and their own theories. The ultimate aim will be to understand how this complex biological system works at both a 'reductionist' molecular and more 'holistic' organ level. As well as being of interest for its own sake, an improved description of this system is likely to have significance for healthcare and industry (in particular for people manufacturing machines that measure parameters relating to oxygen and energetics in the body.