Atpif1 gene regulates heme synthesis in red blood cell formation

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.

"We believe that the two iron-two sulfur (2Fe- 2S) cluster of ferrochelatase allows it to sense certain metabolic fluxes in the cell and respond to those fluxes in an appropriate way," said Dailey, who is a professor of microbiology and director of the UGA Biomedical and Health Sciences Institute. "When Atpf1 is deficient, there is a change in the mitochondrial pH/redox potential. This change is sensed by the cluster, and ferrochelatase activity is turned down, which results in diminished heme synthesis."
The researchers also were able to produce data on the human version of Atpif1, noting its functional importance for normal red blood cell differentiation as well as how a deficiency may contribute to human diseases-such as congenital anemias and disorders related to dysfunctional mitochondria, the organelles that power the cell.
Overall, Dailey believes the study's results will impact the field of red blood cell development significantly with the establishment of the ferrochelatase [2Fe-2S] cluster as a new regulatory component in heme synthesis. New areas of investigation will open, he said, and the molecular basis of currently undefined red blood cell-based syndromes and diseases may be revealed.
Source: University of Georgia

Atpif1 gene regulates hemoglobin synthesis during red blood cell formation

Researchers at Brigham and Women's Hospital (BWH) have discovered a new gene that regulates hemoglobin synthesis during red blood cell formation. The findings advance the biomedical community's understanding and treatment of human anemias and mitochondrial disorders.
The study will be published online on November 7, 2012 in Nature.
The researchers used an unbiased zebrafish genetic screen to clone mitochondrial ATPase inhibitory factor-1 gene, or Atpif1. The gene allows animals-zebrafish, mice and humans for instance-to efficiently make hemoglobin. Hemoglobin is the protein in red blood cells responsible for transporting oxygen in the blood.
The researchers found that loss of Atpif1 causes severe anemia. Moreover, the researchers uncovered a broader mechanistic role for Atpif1-regulating the enzymatic activity of ferrochelatase, or Fech. Fech is the terminal enzyme in heme (a component of hemoglobin) synthesis.
"Our study has established a unique functional link between Atpif1-regulated mitochondrial pH, redox potential, and [2Fe-2S] cluster binding to Fech in modulating its heme synthesis," said Dhvanit Shah, PhD, BWH Division of Hematology, Department of Medicine, first study author.
The researchers were also able to produce data on the human version of Atpif1, noting its functional importance for normal red blood cell differentiation, and noting that a deficiency may contribute to human diseases, such as congenital sideroblastic anemias and other diseases related to dysfunctional mitochondria (the energy powerhouses of cells).

"Discovering the novel mechanism of Atpif1 as a regulator of heme synthesis advances the understanding of mitochondrial heme homeostasis and red blood cell development," said Barry Paw, MD, PhD, BWH Division of Hematology, Department of Medicine, senior study author.
Shah and Paw continue to identify new genes responsible for hematopoietic stem cell development and red cell differentiation. Their identification of new genes will elucidate the new mechanisms regulating hematopoiesis-the formation of blood cell components. Their work not only provides greater insight into human congenital anemias, but also new opportunities for improved therapies.
Anemia, a condition in which your blood has a lower than normal number of red blood cells or hemoglobin levels, can affect people of all ages. Women of childbearing age and older adults are at higher risk. Babies and children are also at risk for anemia due to nutritional iron deficiency or lead poisoning.
Source: Brigham and Women's Hospital

Patient Profile: Khai - Healing, Halfway Around the World

When Heather and Aaron Ayris decided to welcome a nine-year old boy with thalassemia into their home for six weeks, they hoped their hospitality would help improve his health. They wanted to show their guest a good time and lift his spirit.
But it’s the Ayris family whose lives were changed – and it all began in May 2009, as soon as they met nine-year old Khai at the airport in Charlotte, North Carolina.    

“I am quite certain that, at that moment in the airport, as I hugged him, he became a part of our family - no words needed,” Heather said.

Khai came to the United States from war-torn Afghanistan through a non-profit organization that organizes medical and dental care for impoverished Afghan children. He was placed with the Ayris family, who had volunteered to host him.  Khai had struggled with thalassemia for his entire life, receiving transfusions but no medications. So, within just a few days of his arrival, Heather took him to the doctor – and, right away, discovered the challenges they had to confront together.

   

“When we were told he had beta thalassemia major, I calmly asked, ‘What is that?’ The doctor told us is was a severe form of anemia,” Heather explained. “While we knew he was anemic, we were about to learn a lot more about a genetic disease that I’d never heard of before.”

 And so the Ayris family began racing against time to find out – and do – as much as they could for Khai within the six weeks they had with him. Through numerous doctor visits and dozens of tests, they found out that Khai had severe iron overload – the result of years of transfusions without iron chelation medication. 

“The ferritin count in his blood tests was above 13,000, and there was no telling how high the iron concentration was in his organs,” Heather said. “We knew they were at risk for failure. We contacted Khai’s family in Afghanistan and found out that three of his siblings had died from the illness, including his 13-year-old sister who’d recently died of heart failure.”

With that, a race against time became a struggle to save Khai’s life. When she wasn’t visiting physicians with Khai, working or taking care of her two children – A.J. and Cade – Heather was busy researching ways to quickly get Khai’s iron levels under control. But his six-week stay was fast coming to an end.

Just three days before he was scheduled to depart, Khai’s family in Afghanistan agreed that he should stay longer for treatment. The nonprofit organization that had brought him to the United States arranged for a visa extension. A pharmaceutical company approved Khai for participation in an assistance program that gave him access to critical iron chelation medication. And a local hospital pledged to help cover the costs of Khai’s monthly blood  transfusions.

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Everything seemed to be going right in pursuit of better health for Khai – but Heather Ayris kept on researching, looking for better possibilities for the little boy who had become part of their family.

“Over the next few months, I made countless phone calls and sent email, trying to understand more about beta thalassemia major and the concerns with chronic iron overload. Most of the e-mails I sent went unanswered, but one very important e-mail received a reply – from the Cooley’s Anemia Foundation,” Heather explained. “I'm thankful every day for the response from Eileen Scott, Patient Services Manager at Cooley's Anemia Foundation. Every time I called with a tearful question on how to make the treatments less painful for Khai or to celebrate the lowering of his iron counts, she was there!”

With a group effort led by the Ayris family’s love and persistence, Khai’s health is much improved. His ferritin levels are less than half of what they were upon his arrival, and he was recently accepted into a clinical trial for more advanced forms of combined chelation treatment. And equally important for both Khai and his American family, he’s really enjoying his life in North Carolina.

"Khai is in Boy Scouts; he started this past year and really enjoys it.  He’s an ‘outside boy’ and enjoys hiking, nature and working in the yard,” Heather said. “He came to us knowing no English at all and previously was not able to attend school in Afghanistan, so he’s had to get used to formal education here.  He’s now able to read and write and, while he has some catching up to do, he’s definitely on the right track. And we’re all very proud of how resilient all three of our boys – Khai, A.J. and Cade – have been.”

But, even though he’s getting more accustomed to life in the United States – and is benefiting from the level of health care available to him here – Heather Ayris is determined to keep Khai connected to his family in Afghanistan and his roots.

“We try to Skype with Khai's Afghan family every two weeks or so.  We purchased a laptop for them, and Skyping has made a big difference for Khai, being able to see them in person,” Heather explained. “However, because he’s not using his native language (Pashto) frequently, he’s losing his ability to speak and understand it.  That really has made me sad because I don’t want him to lose his heritage.” 

“It’s important for him to remember where he comes from,” she continued. “We shared that concern with Khai’s family, but his father has told us that it doesn’t matter to them.  It’s more important to them to see their child healthy and thriving, and they are just so thankful that he has another family here that loves and cares for him.”

And that’s exactly what Khai has.