So this technology could be dangerous to use to treat mitochondrial diseases.
In two children born as a result of mitochondrial donation, mitochondria with the maternal genotype were found in the cells. In theory, this should not be so: during this procedure, the maternal nucleus is transplanted into a donor egg with a full set of mitochondria. However, in one of the children, about half of the cellular mitochondria turned out to be maternal, and in the other – 72 percent. It turns out that this technology – which is now used to treat mitochondrial diseases – can, on the contrary, lead to the birth of a sick child. First case of such mitochondrial reversal Described In the magazine Fertility and Sterility. The second is not published, about him tells MIT Technology Review.
Mitochondrial donation is now used mainly for mitochondrial diseases. That is, in cases where the expectant mother carries a dangerous mutation in mitochondrial DNA, and a child conceived naturally will inevitably inherit it.
To prevent this from happening, the nucleus is taken from the mother’s egg and transplanted into the donor’s egg, from which the nucleus has been removed. And then fertilized with paternal sperm, as usual. It turns out an embryo with a nuclear genotype from both parents and a mitochondrial genome from a donor – since the cytoplasm of the egg contains donor mitochondria (read about how and why this method was invented in the material “Therapy of Evil”).
In laboratory experiments, this procedure is not always successful: in cell lines obtained in this way, sometimes again appear maternal mitochondria. This phenomenon has been called mitochondrial reversion, and no one really knows how it occurs. But all the reversal reports came from laboratories, and reproductive clinics have not yet published such data. And all the children born after mitochondrial donation – at least those that are known – were healthy.
Now there is the first evidence that mitochondrial reversal is possible and live. One of them was received by a group of scientists led by Dagan Wells from the University of Oxford with the participation of Shukhrat Mitalipov, the head of the first American experiment on editing the human genome.
The authors of the work conducted a pilot study in which mitochondrial donation was used to treat infertility. This method has not yet been proven to be effective and apply only in those countries where reproductive technologies are not regulated very strictly. However, some scientists believe that one of the causes of female infertility may be related to mitochondria – although the exact mutations that are responsible for this are unknown – which means that donation would help to cope with this.
For this trial, doctors selected 25 couples in which women did not suffer from mitochondrial diseases, and men were not diagnosed with infertility, and who underwent 3-11 unsuccessful IVF cycles. In total, they performed 122 procedures, resulting in 19 embryos, of which 7 took root in mothers and 6 were born.
All children had paternal and maternal genes in the nuclear genome and, as expected, no donor genes were found. With the mitochondrial genome, it turned out differently: in five children, it was 99 percent donor, as it should be. But one child was not. When geneticists took his cells for analysis, even at the embryonic stage, before transplanting into the uterus, there was only 0.8 percent of maternal mitochondrial DNA, the rest was donor. But after the birth of maternal DNA, it turned out to be 36-51 percent in the cells of different tissues, and after a few months it was already up to 60 percent in saliva cells.
This is the first clinical trial for mitochondrial donation for infertility — and the first documented case of mitochondrial reversal. live. Meanwhile, the MIT Technology Review journalist drew attention to another such case – Ukrainian embryologist Pavlo Mazur spoke about it back in 2020. At that time he worked in a clinic that developed and practiced this method, and one patient underwent therapy with him again. Her first child was born healthy, with low levels of maternal mitochondrial DNA. But in the second child, by the time of birth, the share of the maternal mitochondrial genome was 72 percent. Mazur spoke about this at an online conference and did not publish this data anywhere.
In both cases, the children were born healthy and developed normally – at least at the time when doctors noticed their mitochondrial reversal. And there was no reason to suspect that the children might develop health problems – since their mothers did not suffer from mitochondrial diseases. However, the very possibility of mitochondrial reversal calls into question the safety of the procedure when it comes to the treatment of mitochondrial diseases.
One can imagine a situation in which maternal mitochondria, which entered the egg along with the nucleus, win in competition with donor ones. And then the child will be born with mitochondrial mutations – and, possibly, will get sick. At the same time, it may not be possible to track this immediately after fertilization and select a healthy embryo. In at least these two described cases, the reversal was noticed already after birth, i.e., competition between the two types of mitochondria occurred after implantation.
True, in order to assess the degree of this risk, scientists will have to understand the mechanisms of mitochondrial reverse in more detail. It is possible that mitochondria with mutations will behave somehow differently than healthy ones. In addition, since reversal occurs simultaneously in many cells of the embryo independently, it can be of different strength in different tissues. And then some of the organs can turn out with maternal mitochondria, and some without, which can also affect the health of the child.
Earlier we told another story about the competition of mitochondria – then scientists suspected that the child inherited them from the father, which usually does not happen. True, later this hypothesis was refuted – paternal mitochondria turned out to be a genetic illusion.
