WHAT ROLE DO FERRITIN-LIKE PROTEINS PLAY IN BACTERIA?

Iron (as ferrous ion) is required for growth and physiological processes in most bacteria. In addition, the virulence of many food borne pathogens has been associated with the ability to sequester iron from its environment and/or its host. However, iron in excess of that needed by the cell is toxic and potentially lethal to bacteria. Therefore, bacteria have evolved a strategy which involves the use of ferritin-like molecules to protect cells from the harmful effects of excess iron.

When ferrous ions react with metabolically generated hydrogen peroxide, very reactive and toxic hydroxy radicals are produced. Hydroxy radicals can induce oxidative stress through lipid peroxidation, DNA strand breaks and degradation of various biomolecules with eventual death of the cell. Bacteria synthesize ferritin-like iron storage proteins to remove excess ferrous ions from the cytoplasm, thereby minimizing cell damage. The bacterial ferritins and bacterioferritins are related to the ferritins of eukaryotes and both the eukaryotic and prokaryotic ferritins have a common evolutionary origin. The bacterial ferritins are more closely related to the mammalian ferritins than are the bacterioferritins. Bacterioferritins differ from the ferritins by the presence of heme groups (generally iron protoporphyrin IX). The ferritin-like proteins have a molecular mass of ~450 kDa, made up of 24 subunits that form a hollow sphere. Ferrous ions are taken up by the ferritin-like molecules, oxidized to ferric ions which are then stored in the central cavity of the molecule. Thus, ferritin permits the storage of iron in a soluble, non-toxic form which can be used as a source of iron during periods of iron deficiency.

While a number of bacteria produce bacterioferritin and/or bacterial ferritin, the role(s) of the ferritin-like compounds in the physiology of the cell has not been determined in many bacterial species. The utilization of mutants lacking the ability to synthesize ferritin-like compounds has demonstrated that ferritins and bacterioferritins are quite varied in the mode of action in the bacterial cell.

Bacterial ferritin.

Insertional inactivation mutants of the Campylobacter jejuni ferritin gene are unable to grow in iron-deficient media whereas in iron-containing media the mutant grows similarly to the wild type. In addition, growth of the mutant is inhibited by hydrogen peroxide, indicating that ferritin is able to protect C. jejuni against oxidative stress through removal of toxic ferrous ions. The lack of growth of the ferritin-deficient mutant in the absence of ferrous ion indicates that the iron in bacterial ferritin can be used as an iron source. Inactivation of the Escherichia coli ferritin-A gene has shown that the iron stored in bacterial ferritin-A can be utilized by E. coli during iron limitation. However, unlike the ferritin of C. jejuni, the E. coli ferritin does not protect the cells against oxidative stress induced by hydrogen peroxide. A completely different picture is seen in Helicobacter pylori. Studies with mutants indicate that the ferritin of H. pylori does not serve as a source of iron for cellular growth nor does it protect the cells against hydrogen peroxide stress. Interestingly, certain levels of ferrous (1 mM) or ferric (2 mM) ions inhibit the growth of the ferritin-less mutant of H. pylori; these levels of metallic ions do not prevent the growth of the parental type. Thus, the apparent role of ferritin in H. pylori is not to protect against oxidative stress or to serve as a source of iron, but rather it is to protect the cells against iron overload.

Bacterioferritin.

Growth of Neisseria gonorrhoeae is reduced in low-iron medium if the gene for the synthesis of bacterioferritin-A is deleted. In addition, the mutant is more sensitive to hydrogen peroxide. Thus, bacterioferritin-A can be a source of iron for N. gonorrhoeae and can protect the cells against oxidative stress. The bacterioferritin of Brucella melitensis does not protect the cell against hydrogen peroxide stress; however, its role as a source of iron has not been studied. The bacterioferritin of E. coli does not protect the organism against oxidative stress, nor is the stored iron a source of iron for growth. In fact, E. coli bacterioferritin is limited as a storage depot of iron since <1 % of cellular iron is found in bacterioferritin. In contrast, approximately 50% of the cellular iron is sequestered in the bacterial ferritin.

Conclusions:

A survey of ferritin-like compounds in bacteria presents a confusing picture. Depending on the bacterial species, the iron stored in ferritin-like compounds can be used as a source of the metal during iron starvation, the ferritin-like compounds can take up excess ferrous ions and thereby protect the cell against oxidative stress, and/or ferritin-like compounds can store excess iron to protect the bacterial cells against iron overload. It is probable that ferritin-like compounds are produced by most bacterial species. Ferritin-like compounds have been found in Azotobacter vinelandii, Listeria monocytogenes, Mycobacterium paratuberculosis, M. avium, M. leprae, M. tuberculosis, Staphylococcus aureus, Yersinia pestis and Bacteroides fragilis. However, in these organisms, no studies have described the role of the ferritin-like compounds. More studies, particularly with null mutants, are needed to define the metabolic role of the ferritin-like compounds in bacteria.

There is no information concerning the role that ferritin-like compounds might play in the survival of bacteria in environments such as food, soil and water. Information is also lacking concerning the contribution of ferritin-like compounds to the disease potential of pathogens.

READING LIST:

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Author: James L. Smith, Ph.D. (James.Smith@ars.usda.gov)
Editor: Mark L. Tamplin, Ph.D.