Iron Deficiency Sparks Dramatic Changes In Gene Expression
DURHAM, N.C. - Researchers at Duke University Medical Center have demonstrated for the first time what happens inside a cell when it is deprived of the essential nutrient iron. Iron is found abundantly in red meats, shellfish dried fruits, whole grains, spinach, seeds and other foods.
Their study in yeast cells demonstrated that iron-starved cells preserve the little iron they possess by shutting down the major iron users in order to maintain the cell's essential functions, said Dennis J. Thiele, Ph.D., professor of Pharmacology and Cancer Biology at Duke. He said their discovery could aid in the diagnosis and ultimately the treatment of serious disorders caused by low iron levels.
Results of his study, funded by the National Institutes of Health, are published in the Jan. 14, 2005, issue of the journal Cell.
Iron deficiency is the most prevalent and severe nutritional disorder world wide, affecting more than 2 billion people. The most widely recognized symptom is anemia, in which too few red blood cells are produced, and the body is deprived of oxygen needed for energy metabolism. Iron deficiency causes wide-ranging symptoms from fatigue, weakness and cognitive deficits to serious heart complications and developmental disorders. Iron deficiency also contributes to the pathology of hereditary blood disorders, Parkinson's disease and certain cancers and develops during a number of chronic diseases, the researchers said.
Until now, however, a cell's response to iron deprivation was poorly understood. In the Duke study, Thiele and his Duke colleagues at the Sarah W. Stedman Nutrition and Metabolism Center demonstrated that the activity of more than 80 different genes was dramatically reduced in response to iron deprivation. The function of many of these genes is unknown, meaning that side effects from iron deprivation may go unattributed to their root cause. Other genes affected by iron starvation are known to be vital in generating energy, copying the cell's genetic code and protecting the cell from free radicals and aging, said Thiele.
"We discovered that iron deprivation actually reprograms the metabolism of the entire cell," said Thiele. "Literally hundreds of proteins require iron to carry out their proper function, so without this nutrient, there is a complete reorganization of how cellular processes occur."
The cellular player responsible for the metabolic reprogramming is a protein called Cth2. Thiele's team found that iron-deprived cells overproduce Cth2. This protein binds to the gene expression machinery of more than 80 different genes and targets these molecules, called messenger RNA, to be destroyed or degraded. Without messenger RNA, a gene cannot translate its genetic code into proteins that carry out its intended functions.
Thiele said the same scenario may occur in human cells, as well, to an even greater degree. His study was conducted in yeast cells because their genome is remarkably similar to that of a human cell. In fact, the Cth2 protein in yeast is quite similar to a family of three proteins in humans. When the human proteins are substituted in place of Cth2 in yeast, they actually assume its function in yeast cells, said Thiele.
"Yeast cells illuminate for us what to look for in human cells," said Thiele. "Current diagnostic markers for iron deficiency aren't very sensitive, unless the deficiency is severe. Pinpointing the genes affected by iron deprivation should provide us with a genetic fingerprint of what patients with varying levels of iron deprivation look like."
A patient's blood could easily be tested for specific diagnostic markers that would indicate his level of iron deprivation, he said. With diagnostic markers in place, physicians could translate the severity of the disease into the appropriate treatment.
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