Hypoxia as a therapy for mitochondrial disease. - PubMed - NCBI
Defects in the mitochondrial respiratory chain (RC) underlie a spectrum of human conditions, ranging from devastating inborn errors of metabolism to aging. We performed a genome-wide Cas9-mediated screen to identify factors that are protective during RC inhibition. Our results highlight the hypoxia response, an endogenous program evolved to adapt to limited oxygen availability. Genetic or small-molecule activation of the hypoxia response is protective against mitochondrial toxicity in cultured cells and zebrafish models. Chronic hypoxia leads to a marked improvement in survival, body weight, body temperature, behavior, neuropathology, and disease biomarkers in a genetic mouse model of Leigh syndrome, the most common pediatric manifestation of mitochondrial disease. Further preclinical studies are required to assess whether hypoxic exposure can be developed into a safe and effective treatment for human diseases associated with mitochondrial dysfunction.
Defects in the mitochondrial respiratory chain (RC) underlie a spectrum of human conditions, ranging from devastating inborn errors of metabolism to aging. We performed a genome-wide Cas9-mediated screen to identify factors that are protective during RC inhibition. Our results highlight the hypoxia response, an endogenous program evolved to adapt to limited oxygen availability. Genetic or small-molecule activation of the hypoxia response is protective against mitochondrial toxicity in cultured cells and zebrafish models. Chronic hypoxia leads to a marked improvement in survival, body weight, body temperature, behavior, neuropathology, and disease biomarkers in a genetic mouse model of Leigh syndrome, the most common pediatric manifestation of mitochondrial disease. Further preclinical studies are required to assess whether hypoxic exposure can be developed into a safe and effective treatment for human diseases associated with mitochondrial dysfunction.
http://www.sciencemag.org/news/2016...tm_medium=twitter&utm_campaign=oxygendep-2589Finally, it is notable that the aging process and virtually
all age-related degenerative diseases are associated with
secondary mitochondrial dysfunction and oxidative stress
(40). While antioxidants have been proposed as a strategy to
alleviate these disorders by scavenging free radicals, our
work suggests that simply limiting the substrate for oxygen
toxicity may prove more effective.
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.
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.
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