Understanding supply and demand for heme in cells

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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.