Understanding supply and demand for heme in cells

血红素是一种小的有机分子，其中心含有铁。没有真核生物能在没有血红素的情况下存活。有成千上万种不同的血红素蛋白，负责氧气运输、电子转移、氧化应激反应、呼吸和各种催化等过程。如此简单的分子可以如此多才多艺，这是大自然的一项惊人壮举，但最近发现，这只是更大的冰山一角。除了以上这些作用外，血红素在细胞信号传导和调节中也很重要。这意味着必须有血红素的供应，超出上述血红素蛋白的供应，这些血红素蛋白可以用于调节用途，并可以对细胞中的短暂需求做出反应。因此，细胞需要将血红素从其合成位置（线粒体）移动到其他相关位置的机制。这就提出了供需方面的后勤问题。首先，血红素不溶于水，所以它需要通过与其他物质（可能是蛋白质）的（可逆）结合来溶解。由于它与氧的反应性，高浓度的它对细胞也是有毒的。因此，细胞不能简单地囤积血红素，然后让它以不受控制的浓度释放出来。但是，虽然血红素合成（8步生物合成途径）和血红素降解（通过血红素加氧酶）的机制是已知的，但两者之间发生的事情——血红素动员和细胞如何管理供应——与40年前提出的基本模型几乎没有改变。我们想要理解这个。血红素位于细胞的什么位置？血红素的局部浓度是多少？它们在不同的条件下会变化吗？血红素何时以及如何移动？我们已经开发了新的技术来监测细胞中的血红素浓度，我们将用它来回答这些问题。我们将建立细胞血红素动力学和动员的详细图片。它将改变我们对血红素在生物学中的使用方式的看法，并将在生物技术应用中具有高度相关性，因为已知细胞血红素浓度的缺乏或过量与健康和疾病有关。

Heme is a small organic molecule containing iron at the centre. No eukaryote has been identified that can survive without heme. There are thousands of different heme proteins, responsible for processes such as oxygen transport, electron transfer, oxidative stress response, respiration, and all kinds of catalysis. It is an amazing feat of Nature that such a simple molecule can be so versatile, but it has emerged recently that this is just the tip of a much bigger iceberg. In addition to these roles above, heme has been identified as important in cell signalling and regulation. This means that there has to be a supply of heme, above and beyond that which is already committed to the aforementioned heme proteins, that can deployed for regulatory use and can respond to transient demands in the cell. Cells thus needs mechanisms to move heme from its place of synthesis (mitochondria) to other relevant locations. This presents logistical problems of supply and demand. To begin with, heme is insoluble in water, so it needs to be solubilised by binding (reversibly) to something else (probably a protein). It is also toxic to cells in high concentrations by virtue of its reactivity with oxygen. So cells cannot simply hoard supplies of heme then let it loose in uncontrolled concentrations. But while the machinery for heme synthesis (an 8-step biosynthetic pathway) and heme degradation (by heme oxygenase) is known, what happens in between - heme mobilisation and how cells manage supplies - has hardly changed from basic models proposed 40 years ago. We want to understand this. Where is heme located in cells? What are local concentrations of heme and do they vary under different conditions? When and how is heme moved? We have developed new technology for monitoring heme concentration in cells, and we will use it to answer these questions. We will build a detailed picture of cellular-heme dynamics and mobilisation. It will change the way we think about how heme is used in biology and it will be of high relevance in biotechnology applications, because deficiencies or excesses in cellular heme concentration are known to be relevant in health and disease.