Oxygen deprivation to treat mitochondrial diseases?
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 yet there are no FDA-approved therapy for any primary mitochondrial disease.
At the core of mitochondrial diseases is they disrupt the way the body makes ATP. Treatments for mitochondrial diseases have therefore aim to boost ATP production. Certain rare and devastating diseases, for example, are caused by mutations in the DNA harbored by mitochondria or the nuclear DNA that controls them. Researchers at Massachusetts General Hospital decide to hunt for new therapies by searching for gene mutation survivors in mitochondrial toxins. They used CRISPR-Cas9 to knockout ~18,000 different genes in human cells that were altered to have the same problems as people with mitochondrial diseases. Their hit is a gene called 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. This study was published on Feb. 25thin Science.
It is unclear why hypoxia helped animals with a version of mitochondrial disease. One possibility 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 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. The team is 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.
Read more: “Hypoxia as a therapy for mitochondrial disease” DOI: 10.1126/science.aad9642
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