Understanding supply and demand for heme in cells

点击翻译按钮获取中文摘要

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.