The interaction between the mitochondria and the nucleus may have consequences for new treatments

According to a study published today in the journal, mitochondria, the "batteries" that produce our energy, interact with the nucleus of the cell in a subtle way. Science.

The study, led by scientists at the University of Cambridge, suggests that the suitability of mitochondrial DNA for nuclear DNA could be important when selecting potential donors for newly approved mitochondrial donation treatment, so to prevent potential health problems later in life.

Virtually all of the DNA that makes up the human genome – the "blueprint" of the body – is contained in the nuclei of our cells. This is called "nuclear DNA". Among other functions, nuclear DNA codes for the characteristics that make us individual and for the proteins that do most of the work in our body.

Our cells also contain mitochondria, often called "batteries" that provide the energy needed for our cells to function. Each of these mitochondria is encoded by a small amount of "mitochondrial DNA". Mitochondrial DNA represents only 0.1% of the entire human genome and is transmitted exclusively from mother to child.

Until now, scientists had thought that mitochondria were easily interchangeable and only served to fuel our body. Thus, the mitochondria of an individual could be replaced by those of a donor without consequence. However, in the first large population study to use data from the UK's 100,000 genome project and its pilot project funded by the National Institute of Health Research (NIHR), researchers compared mitochondrial and nuclear DNA from tens of thousands of people and have discovered that mitochondria can be adjusted to the nucleus.

The researchers studied more than 1,500 mother-child pairs and found that just under half (45%) of individuals in these pairs exhibited mutations affecting at least 1% of their mitochondrial DNA. Mutations in certain parts of mitochondrial DNA are more likely to be transmitted, such as those in the so-called D-loop region, which controls how mitochondrial DNA copies itself. Conversely, mutations in other parts of the mitochondrial DNA were more likely to be deleted, such as code explaining how mitochondria produce their own proteins.

"Children inherit exclusively their DNA from their mothers and we wanted to understand how this explains the origin of mitochondrial diseases," said first author, Dr. Wei Wei of the Council's Mitochondrial Biology Unit. Medical Research Center (MRC) and the Department of Clinical Neuroscience of the University. from Cambridge. "What we have discovered is that there is some sort of ongoing selection when mitochondrial DNA is transmitted during a generation, allowing some mutations to be passed on. and block others. "

The team discovered that previously observed genetic variants around the world were more likely to be transmitted than new ones. This implies that there is a mechanism that filters mitochondrial DNA when it is transmitted from mother to child, which influences the likelihood that a particular variant will become established in the human population.

DNA can give us clues about our ancestors – for example, the structure of genetic variants in the DNA of an individual might be more common in people of European descent than in the people of Asian origin. In most people, the genetic variants of our nuclear and mitochondrial DNA come from the same part of the world. However, in about one in 40 people in the UK sample, mitochondrial DNA and nuclear DNA did not have identical ancestors. For example, nuclear DNA could be European while mitochondrial DNA would be Asian. This happens because at one point in the maternal line, there was a mother of different ethnic origin.

"Since mitochondrial DNA has a much higher mutation rate than nuclear DNA, mutation of the mitochondrial genome is a common phenomenon, and we wanted to study the natural selective forces that determine the fate of these mutations," he says. Dr. Ernest Turro of the Department of Hematology. and the CRM Biostatistics Unit and one of the main authors of this study.

"Our statistical analysis suggests that, in individuals with different mitochondrial and nuclear ancestries, recent mitochondrial mutations are more likely to have been observed previously in populations of nuclear ancestry identical to those in the US." mitochondrial ancestry ".

Crucially, these results suggest that changes in our mitochondrial DNA are formed by our nuclear DNA.

"This discovery shows us that there is a subtle relationship between mitochondria and nuclei in our cells that we are just beginning to understand," says Professor Patrick Chinnery, head of the University's Department of Clinical Neuroscience. from Cambridge and Director of Wellcome Trust Researcher. "This suggests to us that the exchange of mitochondria may not be as simple as simply replacing the batteries of a device."

The evidence mirrors that of previous studies of fruit flies and mice, where a mismatch between their mitochondrial and nuclear DNAs impacted the lifespan of organisms and caused cardiovascular and metabolic complications later in life (diseases in humans that may include diabetes heart disease, for example).

The findings could have implications for the treatment of mitochondrial donations (also called mitochondrial replacement therapy), says Professor Chinnery, who has previously worked with the University of Newcastle team in the development of this treatment. This technique is now allowed in the UK to prevent mother-to-child transmission of potentially devastating mitochondrial diseases. This involves substituting a mother's nuclear DNA for a donor egg while retaining the mitochondria of the donor.

"Mitochondrial replacement therapy is an important new treatment allowing mothers to have children without terrible diseases caused by severe mutations in mitochondrial DNA," said Professor Chinnery.

"Our work suggests that we need to carefully examine this new treatment to ensure that it will not cause unexpected health problems." This could mean that doctors will need to match the nuclear genome and the mitochondrial genome of similar mitochondrial donors to an organ transplant ".

The team has now begun to examine people whose mitochondrial DNA does not match their nuclear DNA to determine if this mismatch increases the likelihood that they will be affected by health problems later in life.

This research is the first major population study based on data collected from the 100,000 genome project, which collects genetic data from patients through the NHS in order to transform the way people are cared for and to constitute a new major resource for medical research. . Pilot data for the study was collected through the NIHR Cambridge Biomedical Research Center.

"The implication of the 100,000 genome project in major discoveries demonstrates the importance of large, carefully assembled datasets comprising whole genome sequences, which provide new biological information and pave the way for major transformations of the genome. health system, "says Professor Mark Caulfield, Chief Executive Officer of Genomics England and co-director of the William Harvey Research Institute at Queen Mary University in London.