Naturally-occurring molecule in tree leaves could treat anemia, other iron disorders

Hinoki cypress

“Without iron, life itself wouldn’t be feasible,” says Barry Paw, MD, PhD. “Iron transport is very important because of the role it plays in oxygen transport in blood, in key metabolic processes and in DNA replication.”

Although iron is crucial to many aspects of health, it needs the help of the body’s iron-transporting proteins. Which is why new findings reported in Science could impact a whole slew of iron disorders, ranging from iron-deficiency anemia to iron-overload liver disease. The team has discovered that a small molecule found naturally in Japanese cypress tree leaves, hinokitiol, can transport iron to overcome iron disorders in animals.

The multi-institutional research team is from the University of Illinois, Dana-Farber/Boston Children’s Cancer and Blood Disorders Center, Brigham and Women’s Hospital and Northeastern University. Paw, co-senior author on the new paper and a physician at Dana-Farber/Boston Children’s, and members of his lab demonstrated that hinokitiol can successfully reverse iron deficiency and iron overload in zebrafish disease models.

“Amazingly, we observed in zebrafish that hinokitiol can bind and transport iron inside or out of cell membranes to where it is needed most,” says Paw.

This gives hinokitiol big therapeutic potential.

Iron regulation is essential to health

Red blood cells  require iron to function properly.

Many human diseases of iron deficiency or overload result from loss of the protein function — either hereditary or acquired — that is responsible for ferrying iron across cellular membranes, subcellular compartments and mitochondrial membranes.

Liver affected by iron overload, an example of iron disorders
Iron overload can be dangerous for organs like the liver.

“Like most things in life, too much or too little of a good thing is bad for you; the body seeks homeostasis and balance,” says Paw.

Iron is needed so that the body can produce hemoglobin, a protein that carries oxygen in the blood of vertebrates. But if the body’s iron-transporting proteins are absent, iron can’t get where it’s needed to help make hemoglobin: across cell membranes and inside the cells’ mitochondria.

“Red blood cells are the number one type of tissue in the body that need iron, so if iron-transporting proteins are missing, anemia can result,” says Paw. “Iron-deficiency anemia is the most common nutritional problem in the world.”

On the flip side, it’s not good if too much iron builds up inside cells. Iron overload can cause tissue damage, DNA damage and life-threatening organ dysfunction across the heart, liver and pancreas. This can be caused by a hereditary lack of iron-transporting proteins or from receiving frequent blood transfusions, which are often necessary during treatment for many different medical conditions.

A totally new approach to treating iron-transport disorders

“If you’re sick because you have too much protein function, in many cases we can do something about it. But if you’re sick because you’re missing a protein that does an essential function, we struggle to do anything other than treat the symptoms,” said the paper’s co-senior author Martin Burke, MD, PhD, who led team members from University of Illinois. “It’s a huge unmet medical need.”

Burke’s team initially found that hinokitiol could transport iron across cell membranes in vitro. Then, they sought collaborators like Paw to test its efficacy in animal models.

Zebrafish showing hemoglobin production: Hinokitiol can bypass iron disorders to promote hemoglobin production
A special dye reveals hemoglobin production in a healthy zebrafish (left), an anemic zebrafish (middle) and an anemic zebrafish treated with hinokitiol (right).

In mammalian cell cultures, as well as zebrafish, mice and rats, Paw and collaborators saw that hinokitiol molecules can bind to iron atoms and move them across cell membranes and into/out of mitochondria, despite an absence of the native proteins that would usually carry out these functions.

“If there is a genetic error, cell membranes won’t open for iron to come across,” says Paw. “But when you administer hinokitiol, it combines with iron and ferries it into, within or out of the cells and mitochondria where iron is needed. It’s a very interesting small molecule that has a lot of therapeutic potential!”

The National Institutes of Health and the Howard Hughes Medical Institute supported this work.