A natural heme deficiency exists in biology that allows nitric oxide to control heme protein functions by regulating cellular heme distribution

Abstract

A natural heme deficiency that exists in cells outside of the circulation broadly compromises the heme contents and functions of heme proteins in cells and tissues. Recently, we found that the signaling molecule, nitric oxide (NO), can trigger or repress the deployment of intracellular heme in a concentration-dependent hormetic manner. This uncovers a new role for NO and sets the stage for it to shape numerous biological processes by controlling heme deployment and consequent heme protein functions in biology.

Keywords: anemia; evolution; heme; iron; nitric oxide; physiology.

Figure 1.. Relative iron and heme distribution in mammals.

See text for details.

Figure 2.. Model of NO-driven cellular heme allocation.

The example depicts one way that NO may drive heme allocation in cells, in this case to promote assembly of its receptor heme protein soluble guanylyl cyclase (sGC heterodimer). Cell-generated NO from NO synthase (left) diffuses into a neighboring cell (right) to promote heme allocation into an apo-sGCβ subunit in complex with chaperone hsp90. One way the NO might promote transfer of heme (red parallelogram) from GAPDH is by binding to the heme iron (Fe) (center, red arrow). The incorporation of heme-NO into the apo-sGCβ subunit prompts it to dissociate its GAPDH and hsp90 partners and bind an sGCα subunit (green) to generate a functional sGC heterodimer whose cGMP production can drive numerous biological responses.

Figure 3.. Relationships between NO, heme protein heme content, function, and health and disease.

Panel A depicts how the heme content and function of cellular heme proteins changes with NO concentration due to a hormetic effect of NO on cell heme allocation. A heme anemic condition is present and associated with a suboptimal NO concentration range, in which cellular heme proteins are not fully heme-replete and thus have suboptimal function. Importantly, this heme anemic condition appears to be the natural state. An increase in NO can improve heme allocation and heme protein function, but beyond an optimal concentration the NO gradually loses its ability to promote cellular heme allocation. Panel B depicts four points on the curve (designated 1–4) as examples of where human or animal populations could exist. Some set points likely populate within a “healthy” range (points 1 and 2), while some set points may populate below or above the healthy range (points 3 and 4) and may be associated with or enable disease. See text for details.