Mitochondrial and nuclear DNA mismatch may impact ageing

The interaction between mitochondrial and nuclear DNA may have implications for health, metabolism and ageing, according to a new study.

The findings, which were published in Nature, could inform how the recently approved technique of mitochondrial donation is performed (see BioNews 792).

'The key to this study was understanding how the combination and interaction of our two genomes – the nuclear and the mitochondrial – triggers a cellular adaptation with repercussions throughout our lives,' said Dr Ana Latorre-Pellicer of the University of Santiago de Compostela and the first author of the paper. 

The researchers created mice with 'matched' and 'mismatched' nuclear and mitochondrial DNA (mtDNA) from two strains of mice. The new strains of mice were created through 20 generations of selective breeding. The two 'parent' strains had mitochondrial differences approximately equivalent to those between the mtDNA of African and Eurasian people. 

The mice with mismatched mtDNA and nuclear DNA appeared to be healthier and age better. They had a longer median lifespan than the wild-type mice (although their maximum lifespan was not different) and their telomeres shortened at slower rate, which suggests they age more slowly. They had lower incidence of tumours, lower cholesterol, and they did not experience the age-related decline in respiration that was seen in wild-type mice. They also gained less weight than controls, despite having the same diet, and their blood-insulin levels fluctuated less after fasting, suggesting they were more resistant to diabetes.

Despite these positive signs of health, the mismatched animals also had a higher level of reactive oxygen species at a young age, which is normally associated with cellular damage.

'What they are seeing in the mismatched cases is basically an increase in oxidative stress, and that appears to be having generally a beneficial effect on health,' evolutionary biochemist Dr Nick Lane of University College London, who was not involved in the study, told The Scientist.

Dr Lane suggested that the mismatch could cause a cell to experience mild stress. 'A mild stress response, as long as it's not too much, might be good for your overall health,' he explained. This process is known as hormesis.

If these findings translate to humans, then they could have implications for mitochondrial donation – an IVF technique to prevent the transmission of mitochondrial disease from mother to child. In the process, nuclear DNA from the mother is inserted into a donor egg (from which the nuclear material has been previously removed), which is then fertilised.

Despite the fact that this new work indicates beneficial effects on health caused by such mismatching, Professor Doug Turnbull of the University of Newcastle, who has pioneered the technique of mitochondrial donation, still suggests that donors and recipients be closely matched. He told The Economist that the research was done in highly in-bred mice and therefore needs corroboration, and for now all that we know is that mismatching can have 'profound effects'.