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Approaching Iron Overload from A New Angle
Children's Hospital Oakland Research Institute Collaboration Reveals Mechanism Central to Iron Homeostasis

May 14, 2012 – In a landmark study appearing this week in the online Early Edition of the Proceedings of the National Academy of Sciences (PNAS), CHORI Senior Scientist Elizabeth Theil, PhD and her collaborators at Hunter College/ Graduate Center City University of New York and Case Western Reserve University demonstrate for the first time that ferrous iron (Fe2+) binds directly to a ribonucleic (RNA) complex to result in a conformational change that ultimately increases iron synthesis. The study not only has profound implications on our fundamental understanding of how Fe2+ and other metal ions interact with RNA, but also provides a potential model for treating iron-overload and for targeting viruses that use similar mechanisms to bind to RNA.

"We have known for a long time that if you give iron to a cell, or to a person for that matter, it increases the synthesis of ferritin, the nano-molecule responsible for both storing and releasing iron in the body," says Dr. Theil. "Now we know how that happens."

“The results of our study clearly illustrate for the first time the basic genetic mechanism behind iron homeostasis, or how the body protects itself from excess iron.”



"The results of our study clearly illustrate for the first time the basic genetic mechanism behind iron homeostasis, or how the body protects itself from excess iron."

Excess iron is particularly problematic for patients with conditions like sickle cell disease (SCD) or thalassemia, which often require blood transfusions as part of regular treatment. While these transfusions are lifesaving, they also cause a build up of iron in the body.

"Normally, the body produces balanced amounts of repressor protein and activator proteins and mRNA to have just the right amount of ferritin to collect and store and manage the iron in the body's cells," says Dr. Theil. "When you start treating patients with transfusions, we are creating iron in concentrations that are way outside the normal range of what the body is used to managing. The existing mechanisms just do not have the range to fully respond to hypertransfusion iron overload."

“When you start treating patients with transfusions, we are creating iron in concentrations that are way outside the normal range of what the body is used to managing.”
Current iron overload treatments rely on chelation therapy to bind with the excess iron and remove it from the body. Dr. Theil's study, however, has the potential to provide a vital new tool for the treatment of iron overload.

Researchers have known that the increased synthesis of ferritin observed in cells, animals and people involved a noncoding riboregulator in messenger RNA (mRNA) called the iron-responsive element, or IRE, which binds a protein that prevents ferritin synthesis. In the current study, Dr. Theil and her colleagues added Fe2+ in solution to an IRE-RNA complex, which caused conformational changes at two critical protein-binding sites.
"This conformational change effectively switches off the protein that inhibits ferritin synthesis and pulls on the protein that activates ferritin synthesis. The end result is increased ferritin production," says Dr. Theil.

Increasing ferritin production in patients with iron overload would increase the body's ability to mange and the store the iron itself, providing an even longer window before chelation therapy would be required.

While further studies are required to confirm the safety and efficacy of this approach, the study illustrates for the first time the exact mechanism by which iron (Fe2+) increases ferritin production. The study also provides a novel model for controlling viral RNAs that use similar mechanisms.

"Using this model, we could study the mRNA structure of a particular virus in order to develop drugs that would interact with the mRNA to modify the virus's ability to produce a particular protein; that would stop the virus from reproducing and stop the virus infection," says Dr. Theil.

At a minimum, the study provides fundamental knew knowledge about how iron in particular, but metals in general, interact with mRNA, and opens up whole new avenues of research.

“Understanding the basic principle that we clearly demonstrate here - that mRNA can bind to different proteins, depending on whether metabolic iron is bound to it – is a whole new approach that needs to be fully exploited and understood.”

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Thursday, May 17, 2012 2:29 PM

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