Into Thin Air (Mootha Lab)

 A team led by Harvard Medical School and Massachusetts General Hospital investigators has found that the controlled induction of the hypoxia response, the body’s reaction to a reduced level of oxygen in the bloodstream, may relieve the symptoms of one of the most challenging groups of genetic disorders—mitochondrial diseases.

Their report describing experiments in cellular and animal models of mitochondrial disease has been published online in the journal Science.

“We currently lack effective means of treating mitochondrial diseases, of which there are more than 150 different genetic forms, impacting virtually any organ,” said Vamsi Mootha, HMS professor of systems biology, a researcher in the Mass General Department of Molecular Biology and senior author of the Science report.

“We found that activation of the hypoxia response—either genetically or pharmacologically in cells, or by placing mice in a low-oxygen environment—alleviated mitochondrial pathology,” he said. Many mitochondrial diseases appear in infancy or early childhood, but in others symptoms may not appear until adulthood and are often triggered by external stressors such as infection.Although the mitochondria in many organs are defective in these disorders, disease pathology is manifest only in certain tissues. These observations led the researchers to hypothesize that there might be inborn mechanisms for coping with mitochondrial dysfunction.

They created a cellular model in which respiratory chain activity was inhibited by application of a toxin and used the model to test whether disruption of any of about 18,000 different genes alleviated the cellular effects of mitochondrial dysfunction. The top-ranking gene in their analysis was for Von Hippel Lindau factor (VHL), which ordinarily suppresses the cellular response to hypoxia, implying that the body’s natural hypoxia response might protect against mitochondrial injury. The researchers then showed that both cells and embryonic zebrafish that lacked VHL exhibited greater survival in the face of respiratory chain inhibition. Treatment with a chemical that increases the expression of genes involved in the hypoxia response also reduced death from respiratory chain inhibition. The researchers next graduated to rodent studies, using an accurate genetic model of a specific mitochondrial disease. Mootha’s team partnered with Warren M. Zapol, the HMS Reginald Jenney Professor of Anaesthesia at Mass General.