Metabolism: The long-term consequences of ‘mismatching’ mitochondrial and nuclear DNA

Subtle variations in the sequence of mitochondrial DNA can have profound effects on metabolism and ageing, suggests a study in mice published this week in Nature. The finding could have implications for the field of mitochondrial replacement therapy.

Eukaryotic organisms have two repositories of DNA: the nucleus and the many energy-generating mitochondria that surround it in the cell. Jose Antonio Enriquez and colleagues studied specially bred strains of mice that have the same nuclear DNA but different mitochondrial DNA. When the animals were young, there was little obvious effect, but as they aged, the authors noticed differences in mitochondrial function, insulin signalling, obesity and age-related measures including telomere shortening. These differences affected both the health and lifespan of the animals.

Mitochondrial replacement therapy has the potential to prevent the transmission of faulty mitochondrial genes from mother to child and to improve fertility by ‘rejuvenating’ eggs, but the long term effects of ‘mix and matching’ nuclear and mitochondrial DNA from different sources are unknown. With non-disease-causing mitochondrial variants now shown to influence health, the study highlights a need for caution. The authors suggest that in the future, consideration should be given to using donor mitochondrial DNA that is a close genetic match to that of the recipient.