Breathing air containing about half the usual percentage of oxygen can reverse mitochondrial disease in mice.
Previous work by the same team had found that breathing low oxygen before disease onset could extend lifespan and delay symptoms in a mouse model of Leigh disease. However the new study shows that low oxygen can reverse existing damage in mice with advanced Leigh disease.
'We found, much to our surprise and delight, that we could actually reverse advanced disease,' said Professor Vasmi Mootha of the Howard Hughes Medical Institute, who led the study. 'I don't think anybody thought that these types of neurological diseases could be reversible.'
Leigh Syndrome usually appears within the first year of life, although some adult onset forms do exist, and is characterised by a lack of growth and development, and progressive brain lesions and loss of motor skills, with a life expectancy of only three years. There are currently no proven treatments for most forms of the disease.
The team of scientists showed that mice with a version of Leigh Syndrome (the most common paediatric mitochondrial disease) made to breathe air with a low level of oxygen (11 percent) lived an average of 270 days - nearly four and a half times longer than those breathing normal levels of oxygen, which survived only around 60 days.
The findings suggest existing damage including disease-associated behaviour, biomarkers and brain lesions were reversed in the low oxygen mice. Mice which were switched back to normal air after breathing low oxygen air were found to die within a few days, as were mice which were given air containing high oxygen concentrations of 55 percent.
However, breathing air containing 11 percent oxygen - roughly equivalent to the atmosphere at the base camp of Mount Everest - could be difficult to administer and lead to adverse symptoms if given to treat people for a long duration. Therefore Professor Mootha’s team had hoped to see positive effects using an intermediate oxygen concentration of 17 percent, or by switching periodically between normal and low oxygen concentrations. These were both found to be ineffective.
'The disappointing part was that we didn't come up with a more practical regimen, at least in this paper,' said Professor Mootha. 'We are not ready yet to go into the clinic.'
The team did not find how hypoxia – a deficiency in the amount of oxygen reaching the tissues, caused by breathing low oxygen air – causes the benefits seen in the mice. Mitochondria use oxygen to produce energy for the cell via a series of proteins called the electron transport chain (ETC). Many of the gene mutations associated with Leigh Syndrome affect the proteins in the ETC, such as the Ndufs4 gene, which encodes the first protein in the chain, and was the gene removed from the mice used in this study in order to model the syndrome.
The study was published in the Proceedings of the National Academy of Sciences (PNAS).