When an iron transport protein is missing, iron builds up on one side of the cell membrane (left). Hinokitiol wraps around iron atoms and transports them across the membrane (right). Graphic by Julie McMahon and Liz Ahlberg Touchstone, University of Illinois
Researchers say they have identified a small molecule that can transport iron when typical transport routes are mutated or absent.
The molecule, hinokitiol, was able to move iron into or out of cells by wrapping around iron atoms and shuttling them across the membrane layer.
Hinokitiol promoted gut iron absorption in rats and mice deficient in iron transport complexes, and it promoted hemoglobin production in zebrafish that otherwise couldn’t transport iron effectively.
The researchers believe these findings, published in Science, may lead to new treatments for disorders associated with iron metabolism, such as anemias and hemochromatosis.
“The long-term therapeutic implications of our work with hinokitiol points to potentially using this chemical to correct anemias caused by genetic deficiencies of iron transporters required for normal red cell formation,” said study author Barry Paw, MD, PhD, of Brigham and Women’s Hospital in Boston, Massachusetts.
“At the same time, hinokitiol has the potential to correct iron-overload syndromes, such as hemochromatosis. More extensive clinical trials are necessary to work out the full potential of hinokitiol and to identify potential toxicities that we have not identified using preclinical models.”
Dr Paw and his colleagues discovered the potential of hinokitiol when screening for a molecule that could restore growth to yeast lacking an iron transporter complex. Hinokitiol is a natural product originally isolated from the Taiwanese hinoki tree.
The researchers found that hinokitiol could transport iron across the yeast cellular membrane in mutant yeasts lacking their major iron uptake transporters. Three hinokitiol molecules can wrap around an iron atom and transport it directly across the membrane where the missing protein should be.
The team also tested hinokitiol in mice, rats, and zebrafish that were missing iron-transport proteins.
Orally administered hinokitiol restored iron uptake in the guts of ferroportin-deficient mice and DMT1-deficient rats, and adding hinokitiol to a tank housing DMT1- and mitoferrin-deficient zebrafish prompted hemoglobin production in the fish.
The researchers also found that hinokitiol restored iron transport in human cells taken from the lining of the gut.
“We found that hinokitiol can restore iron transport within cells, out of cells, or both,” Dr Paw said. “It can also promote iron gut absorption and the creation of hemoglobin in some of our models. These findings suggest that small molecules like hinokitiol that can mimic the biological function of a missing protein may have potential for treating human diseases.”
