A complete model of oxygen consumption by mitochondrial cytochrome c oxidase

我们身体的大部分可用能量来自于氧气对脂肪、蛋白质和碳水化合物的可控燃烧(氧化)。向器官(心脏、大脑等)输送氧气因此，这对健康、增长和发展至关重要。氧气输送或消耗的问题是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。体内几乎所有(95%)的氧气被所有细胞内的一个小器官(细胞器)消耗。这就是线粒体。在线粒体内，一种名为细胞色素c氧化酶(CCO)的蛋白质催化剂(酶)消耗所有的氧气；氧气被转化为水，在线粒体上产生电压，最终用于制造一种名为三磷酸腺苷(ATP)的分子；三磷酸腺苷是所有细胞的通用能量货币，驱动肌肉运动、大脑信号传递、生长、发育和组织修复等。CCO包含许多有色铁和铜中心，使其能够在完好无损的人类体内检测到它，例如，在思考过程中的大脑中，或在运动中的肌肉中。这项资助的目的是研究CCO在体内是如何被控制的，特别是为了提高我们对这些我们可以非侵入性测量的信号的理解。这是一个复杂的问题，我们将通过结合体外(试管)实验和数学建模来解决。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。我们将首先优化对试管中不同颜色信号的测量。然后我们将看看这些信号是如何在体外被控制的。从这一点出发，我们的最终目标是开发一种动态数学模型，该模型将演示如何在全身(在体内)控制它。在这个项目中，我们将专注于一个器官(大脑)，原因有两个；大脑严重依赖氧气生存，并且有大量关于其氧气消耗和向大脑输送的体内数据。我们理解这一复杂系统的一个关键部分是理解它在一系列水平上是如何工作的。因此，我们将建立模型，说明氧是如何在CCO本身、线粒体内的CCO和整个大脑的CCO中消耗的。我们将在每个组织级别使用适当的实验来定义和测试该模型是如何工作的。特别是，我们将要求来自世界各地的同事对我们的模型进行批判性的分析，包括他们的数据和他们自己的理论。最终目的将是了解这个复杂的生物系统是如何在“简化论”分子和更“整体”的器官水平上工作的。除了本身的意义之外，对这一系统的改进描述可能对医疗保健和工业(特别是对制造测量与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.