Malfunctioning of the mitochondria can lead to metabolic disorders in the person affected. Furthermore, mutations in the mitochondrial DNA (mtDNA) are causing muscle weakness, neurodegenerative diseases, cardiac disorders as well as diabetes, and are linked to the ageing process. But how and when is the proportion of pathogenic mtDNA mutations that will be inherited determined? Up to now there has been no suitable model system available to explore this question. Max Planck researcher Christoph Freyer has developed a new model and, together with an international research team, has got some answers: Intra-family differences in the degree of mutation of the mitochondrial genes are largely established before the mother herself is born.
The genetic blueprint of a living organism is predominantly held in the cell nucleus, in the form of DNA. However, the mitochondria of a cell also carry hereditary information of their own. This is referred to as “mtDNA”. Since the mitochondria play a central role in energy supply within the body, mutations in the genes of the mtDNA can have a serious effect on health. The respective disease can also be passed down to the next generation via the mutated genes, but only the maternal mtDNA is transmitted.
Opinions have been divided as to exactly how and when health-endangering mitochondrial mutations are inherited, as the transmission of mtDNA does not follow the classic Mendelian laws of inheritance whereby both mother and father contribute to each piece of hereditary information. This prompted Christoph Freyer, research scientist at the Max Planck Institute for Biology of Ageing in Cologne and the Karolinska Institute in Stockholm, to develop a new mouse model: The main player here is a pathogenic, i.e. a disease-inducing mutation in a mitochondrial gene known as “tRNA methionine”. Mutations in mitochondrial tRNA genes cause a high percentage of the known mitochondrial diseases, although tRNA genes constitute only a fraction of the total mtDNA. This discrepancy has never been satisfactorily explained.
With the aid of tRNA methionine, Freyer has been looking at the ratio of mutated to non-mutated genes, or mutation level, in three different phases of the hereditary process: First he analysed germ cells from mouse embryos and established how the degree of mutation varies from germ cell to germ cell. After birth he looked at that degree in the immature egg cells of the mouse. And later he examined the degree of mutation in the mtDNA of the offspring.
These basic research findings uncover a feature of maternal genetics that may pave the way to novel possibilities for genetic diagnosis
Freyer’s main breakthrough was to show that in contrast to the protein-coding genes, shown by recent research to be subject to prenatal selection, tRNA genes are not selected out by the female germ line. So whether and to what extent mutant genes can be transmitted to the next generation is decided when the future mother is still herself an embryo, during the development of her germ cells. Mutant genes often coexist with normal genes, a condition called heteroplasmy, in the affected egg cells. In other words, mutated and non-mutated genes occur in each egg cell in a particular ratio and thus the mutation may or may not be transmitted to the next generation. This also explains the differences arising within a family.
With these scientific findings, the researchers uncovered a feature of maternal genetics that may pave the way to novel possibilities for genetic diagnosis.
Moreover, the observation that in this model, too, the mice mitochondria try to compensate potential defects caused by mutations provides further insight into the hereditary mechanisms underlying mitochondrial disease. “Perhaps,” suggests Freyer, “this compensation could be stimulated by medical means.” The young researcher plans to use his mouse model in future to test therapies that could possibly prevent the hereditary transmission of mtDNA mutations.