Atpif1 gene regulates heme synthesis in red blood cell formation

Published on November 14, 2012 at 12:07 AM · No Comments

Scientists at the University of Georgia, Harvard Medical School and the University of Utah have discovered a new gene that regulates heme synthesis in red blood cell formation. Heme is the deep-red, iron-containing component of hemoglobin, the protein in red blood cells responsible for transporting oxygen in the blood.

The study was published online Nov. 7 and will be in the Nov. 22 print edition of the journal Nature. The findings promise to advance the biomedical community's understanding and treatment of human anemias and mitochondrial diseases, both known and unknown.

The gene-known as mitochondrial ATPase inhibitory factor-1 gene or Atpif1-was uncovered from a chemical mutagenesis screen of zebrafish, an organism which shares many of the same genes that regulate blood development in humans.

"With zebrafish, we are able to accelerate natural disease processes and screen for many more mutations in blood than we could ever see in random circumstance of human patients," said study senior co-author Dr. Barry Paw, a hematologist and associate professor of medicine at Harvard Medical School.

"In our case, we were looking for mutants that were bloodless, presumably because whatever gene that was inactivated by the random mutation must be critical for blood development, if one of these embryos were bloodless."

That is what Paw and his team found when they stumbled upon the particular "bloodless" mutant zebrafish called pinotage. The loss of the Atpif1 gene was the cause of the fish's severe anemia.

The next step for the team was to determine if the anemia was a defect of iron metabolism or heme homeostasis. Collaborating with molecular biologist Jerry Kaplan at the University of Utah, the researchers discovered a possible link between Atpif1 and ferrochelatase, the terminal enzyme in heme synthesis.

UGA microbiologist Harry Dailey, a leading authority in the structure and function of ferrochelatase, was brought on board. Collaborative work between the Paw and Dailey laboratories uncovered a broader mechanistic role for Atpif1 in regulating the enzymatic activity of ferrochelatase.

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