Award details

Understanding supply and demand for heme in cells

Reference	BB/W007908/1
Principal Investigator / Supervisor	Professor Emma Raven
Co-Investigators / Co-Supervisors
Institution	University of Bristol
Department	Chemistry
Funding type	Research
Value (£)	705,076
Status	Current
Type	Research Grant
Start date	01/03/2023
End date	28/02/2027
Duration	48 months

Abstract

Heme is essential for the survival of virtually all living systems - from bacteria, fungi and yeast, through plants to animals. In the last few years, heme has been shown to have an important regulatory role in cells, in processes such as transcription, regulation of the circadian clock, and the gating of ion channels. To act in a regulatory capacity, heme needs to move from its place of synthesis (in mitochondria) to other locations in cells. Whilst this concept is broadly acknowledged, how it happens is has remained unknown. Hence, while we know in detail how the heme lifecycle begins (heme synthesis), and how it ends (heme degradation) what happens in between is almost completely blank. This is important if we are to understand, and then to control, heme-dependent regulatory process. New approaches are needed to precisely quantify heme distributions and patterns of heme movements across sub-cellular compartments. Our hypothesis, based on considerable preliminary data, is that a proportion of the total heme complement of the cell (which we have named "exchangeable heme") can be mobilised discretely and specifically, with a level of control that provides a mechanism for heme-dependent regulation as well as protection against the deleterious effects of excess heme at high concentrations. We have designed a new fluorescent heme-responsive sensor (mAPXmEGFP) that can precisely quantify heme concentrations - in different cellular locations and in real time. We will use this sensor along with fluorescent lifetime imaging and other fluorescent heme-binding probes to build a detailed picture of cellular-heme dynamics and mobilisation. We will identify where heme is located, what the concentrations are, how and when heme moves around in cells, and how heme distributions vary in response to local changes in heme concentration. These are ambitious questions at the forefront of the discipline. It will change what we understand about the role of heme in biology.

Summary

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.

Committee	Research Committee D (Molecules, cells and industrial biotechnology)
Research Topics	Structural Biology
Research Priority	X – Research Priority information not available
Research Initiative	X - not in an Initiative
Funding Scheme	X – not Funded via a specific Funding Scheme

Associated awards:

BB/W007630/1 Understanding supply and demand for heme in cells

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