Small molecule transports iron in mice, human cells to treat some forms of anemia
A natural small molecule derived from a cypress tree can transport iron into living mice and human cells that lack the protein that normally does the job, facilitating a buildup of iron in the liver and restoring production of hemoglobin and red blood cells, it turns out from a new study.
Born out of a collaboration between researchers from the Urbana Champaign of the University of Illinois, the University of Michigan, Ann Arbor and the University of Modena in Italy, the study showed that the small molecule hinokitiol could potentially function as a “molecular prosthesis.” when the iron-transporting protein ferroportin is missing or defective, providing a potential treatment pathway for ferroportin disease and certain types of anemia.
“This is a truly striking demonstration in a complete animal model that an imperfect mimic of a missing protein can restore physiology and act as a molecular-scale prosthesis,” said co-leader Dr. Martin D. Burke, an Illinois professor of chemistry and a member of the Carle Illinois College of Medicine, as well as a physician. “The implications are really quite broad with respect to other diseases caused by loss of protein function.”
Ferroportin is a protein that forms a channel for the transport of iron in and out of cells. Ferroportin deficiency can be the result of a genetic mutation or caused by inflammation or infection. Patients without the protein have an excessive build-up of iron in the liver, spleen, and bone marrow, especially in a type of cell called a macrophage. Macrophages in the liver chew up old red blood cells and transport the iron in them for recycling into new red blood cells. Without ferroportin, however, the iron accumulates in the cells and can’t be recycled, Burke said.
Removing blood from the body, as is commonly done for other diseases caused by iron buildup, is not an efficient treatment because the buildup is localized and iron levels in the blood are actually low, said study co-author Dr. Antonello Pietrangelo, a professor of medicine in Modena. Pietrangelo was the first to identify genetic ferroportin disease in patients as opposed to a more well-documented form of iron overload that causes iron to build up in the blood serum.
Burke’s group in Illinois detailed hinokitiol’s ability to shuttle iron across cell membranes and correct anemia in zebrafish in 2017, making it a potential candidate for therapeutic application. In the new study, published in the journal PNASresearchers studied the action of hinokitiol in live mice lacking the gene for ferroportin, as well as in macrophages from patients with ferroportin disease.
Professor Young-Ah Seo’s research group of Michigan, who studies genetic disorders of iron and manganese, provided proof-of-concept that hinokitiol could improve anemia in mice.
“We saw that the mice treated with hinokitiol reduced iron accumulation in the liver and improved hemoglobin and red blood cell production,” said Seo, a professor of nutritional biochemistry and co-lead author of the study. “These findings suggest that hinokitiol can deliver iron from the liver to the red blood cells and thus improve hemoglobin in mice.”
The researchers noted that while iron distribution was still not normal in mice treated with hinokitiol, hemoglobin and red blood cell levels had improved to the normal range. This indicates that the small molecule, while not a perfect replacement for ferroportin, can effectively target anemia, said Illinois graduate student Stella Ekaputri, the study’s lead author.
“In healthy organisms there is a threshold of functionality. Our goal is to give a little boost so that the threshold is reached,” Ekaputri said. “Although our small molecule is not perfect, homeostasis for hemoglobin is restored. A little boost is enough to overcome the bottlenecks caused by the ferroportin deficiency.”
The researchers dug deeper to understand the mechanisms of how hinokitiol enhanced iron transport and hemoglobin production in mice. They found that hinokitiol bound to iron in the macrophages where it had accumulated and carried the iron out of the cells. Then hinokitiol released the iron to another protein, transferrin, which put the iron back into the normal hemoglobin production cycle, the researchers found.
The researchers confirmed that hinokitiol functioned similarly in human cells by studying its action in liver macrophages from human patients with ferroportin disease.
“Using our patients’ macrophages, we were able to show that hinokitiol can very efficiently remove ‘free iron’ and also iron stores from macrophages from patients with different mutations,” Pietrangelo said. “This, combined with the data in mice showing that hinokitiol is also effective in vivo, opens a completely new avenue for the treatment of this condition.”
Stella Ekaputri et al, A small molecule redistributes iron in ferroportin-deficient mice and patient-derived primary macrophages, Proceedings of the National Academy of Sciences (2022). DOI: 10.1073/pnas.2121400119
Provided by University of Illinois Urbana Champaign
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