Heme controls antioxidants and iron in ferritin
Discovery could improve or create treatments for several chronic illnesses
October 10, 2005-Oakland, CA-- A new study conducted by scientists at Children's Hospital Oakland Research Institute could help researchers develop new treatments for a variety of health conditions that are all related to abnormal iron metabolism. More than one million Americans have abnormal iron levels in their bodies. For example, iron excess can lead to a long list of health problems including diabetes, heart failure, liver cancer, arthritis and severe fatigue.
Ferritin is a protein that stores or releases iron in the body as it is needed. Until now, scientists were convinced that the only way to develop new therapies for treating iron overload was to focus on iron metabolism. But a new study published in the October 10th issue of the Proceedings of the National Academy of Sciences is the first to demonstrate that the ferritin gene can be controlled by heme, and other common antioxidant regulators. Heme is the molecule that activates many protective genes and is also the part of the blood that uses iron to carry oxygen from our lungs to the rest of the body.
Previously, scientists only focused on genes that were regulated by iron for iron related diseases. Now it is clear that heme might be a "master switch" for iron genes, and antioxidant genes, which are the genes that protect and repair damage caused by oxygen radicals. If that mechanism is found, heme could help scientists unravel the cause and cures of several chronic illnesses.
"This new information will dramatically change the way researchers think about solving certain health problems involving iron or inflammation," said Elizabeth Theil, Ph.D., Senior Scientist at Children's Hospital Oakland Research Institute and co-author of the study. "For the first time we understand that ferritin is one of the protective genes the body uses to protect us from the damage caused by oxygen radicals. "
To find out what controlled ferritin genes; scientists studied cultures of liver cells. They found that iron, by itself, was a weak signal by linking different pieces of ferritin DNA to a "reporter" gene and measuring the amount of reporter protein when cells were fed extra iron, heme, or sulforphane. Iron had practically no effect, but with heme or sulforphane much "reporter" was produced.
Scientists discovered that ferritin is a gene with two kinds of genetic controllers: DNA plus mRNA. Iron regulates the mRNA. When the two regulators were combined in the experiment, heme made the cells produce huge amounts of reporter protein - three times more than either one alone. Both DNA and mRNA carry genetic information. DNA is the blueprint, protected in the nucleus, and mRNA is the working copies used to manage day-to-day information and cell work.
"Our research shows that ferritin mRNA is sensitive to iron, ferritin DNA is sensitive to antioxidants like sulforphane and heme coordinates both DNA and mRNA," said Korry Hintze, a postdoctoral fellow at Children's Hospital Oakland Research Institute and co-author of the study. "Now we know that ferritin is central to both iron and oxygen metabolism."
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