Oxygen deprivation counters deadly mitochondrial disease in animals

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Required fields are indicated by an asterisk (*) Email Sign up for our daily newsletter Get more great content like this delivered right to you! Countrycenter_img For most creatures, oxygen is life. But biology is complicated, and researchers hoping to treat diseases in which our cells’ energy-providing machinery is faulty now suggest the opposite may also be true: Depriving cells of oxygen could be a boon to health. The unexpected idea has been tested only in cells and animals so far, but some scientists are already considering whether lowering oxygen levels might treat certain rare but deadly conditions.The strategy—whose mechanisms are not fully understood—emerged from a new study of mitochondria, the energy powerhouses of the cell. When these organelles falter and can’t produce enough energy, the organism they support can be in trouble. Certain rare and devastating diseases, for example, are caused by mutations in the DNA harbored by mitochondria or the nuclear DNA that controls them. Mitochondrial diseases are rare, affecting about one in every 4000 babies born in the United States. Some children suffer from poor growth or muscle weakness; others experience neurological deficits or heart trouble. The need for new treatments is acute. “We’re bereft of any [Food and Drug Administration]–approved therapy for any primary mitochondrial disease, [and we’re] always searching,” says Peter Stacpoole of the University of Florida in Gainesville, who has long cared for patients with these conditions. While the effects of mitochondrial diseases vary, at their core they disrupt the way the body makes ATP, a critical molecule that stores energy and helps move it through cells. Some treatments for mitochondrial diseases aim to boost ATP production, says Michio Hirano, a neurologist at Columbia University, who is running the North American Mitochondrial Disease Consortium, which aims to characterize and test new therapies for mitochondrial diseases. That’s the logical route. But rather than operating with a predetermined strategy, a Boston group chose to begin its hunt for new therapies with a blank slate. Vamsi Mootha, a mitochondrial biologist at Massachusetts General Hospital, his graduate student Isha Jain, and their colleagues used a popular DNA-editing tool called CRISPR to knock out about 18,000 different genes in human cells that were altered to have the same problems as people with mitochondrial diseases. They wanted to see which cells poisoned with mitochondrial toxins could survive when specific genes were wiped out. “We had one blazingly strong hit,” Jain says. It was a gene called the von Hippel-Lindau (VHL) factor, which encodes a protein that puts a brake on the cellular hypoxia response. Deactivating the VHL gene makes animals react as if they’re in a low-oxygen environment, also called hypoxia.In zebrafish with dysfunctional mitochondria, shutting down VHL nearly doubled their lifespan, Jain’s team discovered. They then moved to mice with a version of a human mitochondrial disease called Leigh syndrome. The researchers kept the animals in chronically thin air that’s similar to the oxygen levels people would experience at the peak of Mont Blanc, the tallest mountain in the Alps, which soars nearly 5000 meters above sea level. The hypoxia-treated rodents lived more than 6 months, compared with about 2 months for untreated animals, Mootha and his colleagues report online today in Science. “The results were far more striking than we hoped,” he says.Mootha’s group is still trying to understand why hypoxia helped animals with a version of mitochondrial disease. “It is so counterintuitive. It is truly novel, and with the animal model … it’s absolutely dramatic,” Stacpoole says. One possibility Mootha cites is that while hypoxia inhibits the production of much-needed ATP, it also blunts production of free radicals, harmful molecules that can damage tissues and may cause problems in children with mitochondrial diseases. Another the group is considering is that hypoxia activates alternative ATP production pathways that help the organism function normally.Continuous hypoxia is not practical in people, and depriving cells of oxygen can also fuel cancer. But there may be other ways to harness the pathway that controls hypoxia, for example with certain drugs.  Mootha and his colleagues are also studying whether intermittent hypoxia has the same effects as the continuous version; this would be easier to test in humans, for example by putting people in a low-oxygen tent at night.The potential benefits of hypoxia need to be carefully considered alongside potential harms, notes Stephen Archer, a cardiologist at Queen’s University in Kingston, Canada. Still, he’s open to more animal testing of the idea—and calls on others to be as well, especially given the dearth of treatments for mitochondrial diseases.last_img

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