Mitochondrial Injury in Animal Models Prevented by Lowering Levels of Oxygen Supplied

Researchers investigating mechanisms for coping with mitochondrial dysfunction and disease have found that the body’s natural response to induced low levels of oxygen has a protective effect against mitochondrial injury. The article, by Harvard Medical School and Massachusetts General Hospital (MGH) researchers and titled “Hypoxia as a therapy for mitochondrial disease,” was published in the journal Science.

Mitochondria are cellular organelles that produce the energy (ATP molecules) used by cells in a series of molecular reactions called the mitochondrial respiratory chain. There are several known pathogenic genetic mutations that affect this essential mechanism in metabolism, leading to mitochondrial diseases, which can affect different organs and systems with differing degrees of severity.

Previous research has pointed out that although mitochondria defects can be found in many organs, the pathology usually only manifests itself in certain tissues. This has led to the hypothesis that cellular or molecular mechanisms might protect against mitochondrial dysfunction.

The research team performed a genome-wide screen to identify potential factors that are protective during inhibition of the respiratory chain. In cellular models and an animal model, the zebrafish, researchers observed that the activation of the hypoxia response, a series of responses to limited oxygen availability, protected against mitochondrial toxicity.

Researchers found that the lack of the Von Hippel Lindau factor (VHL) gene, which is involved in the suppression of the cellular response to hypoxia, resulted in improved survival of cells and embryonic zebrafish in response to respiratory chain inhibition. Moreover, treatment with chemicals that increased the expression of genes involved in the hypoxia response reduced death from mitochondrial dysfunction.

The team then investigated these mechanisms in a genetic mouse model of Leigh syndrome, the most common manifestation of mitochondrial disease in children, and observed that chronic hypoxia led to improved survival, body weight, behavior, and neuropathology in the mice.

The researchers highlighted the need for further studies to assess and establish the effectiveness and safety of hypoxic exposure for therapies targeting human mitochondrial diseases.

“Breathing hypoxic air can be dangerous and could reduce oxygen delivery to major organs as well as produce acute and chronic toxicities. Therefore, it’s crucial to perform additional animal studies to determine optimal treatment regimens and long-term safety. Moreover, there are many types of mitochondrial disease, and we have only tested one. Testing additional mouse models will help us determine whether and when it will be feasible to contemplate human trials,” the study’s senior author, Dr. Vamsi Mootha, said in a MGH’s news release.

Mitochondrial dysfunction is also associated with aging and aging-related degenerative diseases. Despite several therapeutic approaches, there are currently no approved treatments for mitochondrial diseases.