Ni2+-uptake in Pseudomonas putida strain S4: a possible role of Mg2+-uptake pump.

Essential metal ion homeostasis is based on regulated uptake of metal ions, both during its scarcity and abundance. Pseudomonas putida strain S4, a multimetal resistant bacterium, was employed to investigate Ni(2+) entry into cells. It was observed that Mg(2+) regulates the entry of Ni(2+) and by this plays a protective role to minimize Ni(2+) toxicity in this strain. This protection was evident in both growth as well as viability. Intracellular accumulation of Ni(2+) varied in accordance with Mg(2+) concentrations in the medium. It was hypothesized that Ni(2+) enters the cell using a broad Mg(2+) pump, i.e. the CorA system, as the CorA inhibitor, i.e. Co(III) Hex, also inhibits Ni 2+ uptake. This led to the inference that Mg(2+)-based protection was basically due to competitive inhibition of Ni(2+) uptake. We also show that Zn(2+) can further regulate the entry of Ni(2+).

Hereditary hemochromatosis: An opportunity for gene therapy

Levels of body iron should be tightly controlled to prevent the formation of oxygen radicals, lipoperoxidation, genotoxicity, and the production of cytotoxic cytokines, which result in damage to a number of organs. Enterocytes in the intestinal villae are involved in the apical uptake of iron from the intestinal lumen; iron is further exported from the cells into the circulation. The apical divalent metal transporter-1 (DMT1) transports ferrous iron from the lumen into the cells, while the basolateral transporter ferroportin extrudes iron from the enterocytes into the circulation. Patients with hereditary hemochromatosis display an accelerated transepithelial uptake of iron, which leads to body iron accumulation that results in cirrhosis, hepatocellular carcinoma, pancreatitis, and cardiomyopathy. Hereditary hemochromatosis, a recessive genetic condition, is the most prevalent genetic disease in Caucasians, with a prevalence of one in 300 subjects. The majority of patients with hereditary hemochromatosis display mutations in the gene coding for HFE, a protein that normally acts as an inhibitor of transepithelial iron transport. We discuss the different control points in the homeostasis of iron and the different mutations that exist in patients with hereditary hemochromatosis. These control sites may be influenced by gene therapeutic approaches; one general therapy for hemochromatosis of different etiologies is the inhibition of DMT1 synthesis by antisense-generating genes, which has been shown to markedly inhibit apical iron uptake by intestinal epithelial cells. We further discuss the most promising strategies to develop gene vectors and deliver them into enterocytes.