For most creatures, oxygen is life. But biology is complex, and researchers hope to treat diseases in which the machinery providing energy for our cells is defective now suggest the opposite may also be true: Depriving cells of oxygen could be a boon to health. The unexpected idea has only been tested in cells and animals so far, but some scientists are already determine whether lowering oxygen levels could treat certain rare but life-threatening conditions.
The strategy whose mechanisms are not well understood-emerged in a new study of mitochondria, the power plants of the cell. When these organelles weaken and can not produce enough energy, they support the body may be in trouble. Some rare and devastating diseases, for example, are caused by mutations in the DNA hosted by mitochondria or nuclear DNA that controls them. Mitochondrial diseases are rare, affecting about one in 4,000 babies born in the United States. Some children suffer from poor growth or muscle weakness; others with neurological deficits or heart problems. The need for new therapies is acute. "We are deprived of [Food and Drug Administration] -approved therapy for primary mitochondrial disease [and we’re] always looking," said Peter Stacpoole the University of Florida in Gainesville, who has long maintained patients with these conditions.
While the effects of mitochondrial diseases vary, at their base, they disrupt the way the body makes ATP, a vital molecule that stores energy and helps to move through the cells. Some treatments for mitochondrial diseases are intended to stimulate the production of ATP, said Michio Hirano, a neurologist at Columbia University, who is running for mitochondrial disease north American Consortium, which aims to characterize and test new therapies for mitochondrial diseases.
This is the logical way. But rather than operating with a predetermined strategy, a group of Boston chose to start his hunt for new therapies with a blank slate. Vamsi Mootha, mitochondrial biologist at Massachusetts General Hospital, his graduate student Isha Jain, and their colleagues used a popular publishing tool called CRISPR DNA to knock out about 18,000 different genes in human cells that have been modified to have the same problems that people with mitochondrial diseases. They wanted to see what poisoned cells with mitochondrial toxins could survive when specific genes have been destroyed. "We had an incredibly strong blow," said Jain. It was a gene called Factor von Hippel-Lindau (VHL), which encodes a protein that puts the brakes on the cellular response to hypoxia. Disabling VHL gene makes animals react as if they are in a low oxygen, also called hypoxia.
in zebrafish with dysfunctional mitochondria, stopping VHL nearly doubled their lifespan, the Jain team found. They then moved to mice with a version of a human mitochondrial disease called Leigh syndrome. the researchers kept animals in chronically thin air that is similar to oxygen levels people experience at the top Mont Blanc, the highest mountain in the Alps, which hovers around 5,000 meters above the level of the sea. the treated hypoxia rodents lived longer than 6 months, against about 2 months for untreated animals, Mootha and his colleagues report online today in Science . "The results were much more striking than we hoped," he said.
group Mootha still trying to understand why hypoxia helped animals with a version of mitochondrial disease. "It is therefore contrary intuition. It is really new, and with the animal model ... it is absolutely dramatic, "said Stacpoole. One possibility Mootha cites is that while hypoxia inhibits the production of much needed ATP, it also dulls the production of free radicals, harmful molecules that can damage tissue and can cause problems in children with mitochondrial diseases. another group plans is that the active hypoxia pathways of ATP production alternatives that help the body function normally.
continuous hypoxia is not practical in people, and depriving cells of oxygen may also fuel cancer. But there may be other ways to exploit the way that control hypoxia, by . example with certain medications Mootha and his colleagues are also studying whether intermittent hypoxia has the same effects as the continuous version, it would be easier to test in humans, for example by placing people in a tent in low oxygen the night.
The potential benefits of hypoxia should be carefully considered alongside the potential dangers, notes Stephen Archer, Queen University cardiologist in Kingston, Canada. However, it is open to animal testing most of the ideas and invites others to be as well, especially given the shortage of treatments for mitochondrial diseases.
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