Importance of iron regulation
Structure of Heme b
; "Fe" is the chemical symbol of iron, "II" indicates its oxidation state.
Iron is an essential bioelement for most forms of life, from bacteria to mammals. Its importance lies in its ability to mediate electron transfer. In the ferrous state, iron acts as an electron donor, while in the ferric state it acts as an acceptor. Thus, iron plays a vital role in the catalysis of enzymatic reactions that involve electron transfer (reduction and oxidation, redox). Proteins can contain iron as part of different cofactors, such as iron-sulfur clusters (Fe-S) and heme groups, both of which are assembled in mitochondria.
Human cells require iron in order to obtain energy as ATP from a multi-step process known as cellular respiration, more specifically from oxidative phosphorylation at the mitochondrial cristae. Iron is present in the iron-sulfur clusters and heme groups of the electron transport chain proteins that generate a proton gradient that allows ATP synthase to synthesize ATP (chemiosmosis).
Heme groups are part of hemoglobin, a protein found in red blood cells that serves to transport oxygen from the lungs to the tissues. Heme groups are also present in myoglobin to store and diffuse oxygen in muscle cells.
The human body needs iron for oxygen transport. Oxygen (O2) is required for the functioning and survival of nearly all cell types. Oxygen is transported from the lungs to the rest of the body bound to the heme group of hemoglobin in erythrocytes. In muscles cells, iron binds myoglobin, which regulates its release.
Iron is also potentially toxic. Its ability to donate and accept electrons means that it can catalyze the conversion of hydrogen peroxide into free radicals. Free radicals can cause damage to a wide variety of cellular structures, and ultimately kill the cell.
Iron bound to proteins or cofactors such as heme is safe. Also, there are virtually no truly free iron ions in the cell, since they readily form complexes with organic molecules. However, some of the intracellular iron is bound to low-affinity complexes, and is termed labile iron or "free" iron. Iron in such complexes can cause damage as described above.
To prevent that kind of damage, all life forms that use iron bind the iron atoms to proteins. This binding allows cells to benefit from iron while also limiting its ability to do harm. Typical intracellular labile iron concentrations in bacteria are 10-20 micromolar, though they can be 10-fold higher in anaerobic environment, where free radicals and reactive oxygen species are scarcer. In mammalian cells, intracellular labile iron concentrations are typically smaller than 1 micromolar, less than 5 percent of total cellular iron.
Electron micrograph of E. coli
. Most bacteria that cause human disease require iron to live and to multiply.
In response to a systemic bacterial infection, the immune system initiates a process known as
iron withholding. If bacteria are to survive, then they must obtain iron from their environment. Disease-causing bacteria do this in many ways, including releasing iron-binding molecules called siderophores and then reabsorbing them to recover iron, or scavenging iron from hemoglobin and transferrin. The harder they have to work to get iron, the greater a metabolic price they must pay. That means that iron-deprived bacteria reproduce more slowly. So our control of iron levels appears to be an important defense against most bacterial infections; there are some exceptions however. TB causing bacterium can reside within macrophages which are an iron rich environment and Borrelia burgdorferi utilises manganese in place of iron. People with increased amounts of iron, like people with hemochromatosis, are more susceptible to some bacterial infection.
Although this mechanism is an elegant response to short-term bacterial infection, it can cause problems when inflammation goes on for longer. Since the liver produces hepcidin in response to inflammatory cytokines, hepcidin levels can increase as the result of non-bacterial sources of inflammation, like viral infection, cancer, auto-immune diseases or other chronic diseases. When this occurs, the sequestration of iron appears to be the major cause of the syndrome of anemia of chronic disease, in which not enough iron is available to produce enough hemoglobin-containing red blood cells.