During this series, Dr Uliana Dorofeyeva – Advisory Clinical Director at International Fertility Group (IFG) and Co-founder, Director of clinical operations at Ovogene, Ukraine, provided a comprehensive overview of Mitochondrial Replacement Therapies (MRT) and the latest advancements in the field.
She discussed how mitochondrial transfer techniques help prevent the inheritance of mitochondrial genetic disorders and address secondary mitochondrial dysfunction. The session covered the most effective MRT techniques, including pronuclear transfer and spindle transfer, emphasizing the importance of precise laboratory protocols and micromanipulation practices.
Mitochondrial Replacement Therapies (MRT) represent one of the most complex and debated advances in modern reproductive medicine. In this event, Dr Uliana Dorofeyeva provided an in-depth explanation of the science behind MRT, its clinical indications, current limitations, ethical considerations, and future directions.
Dr Dorofeyeva explained that mitochondria function as the “battery” of the cell. They generate energy required for cellular activity, tissue function, and overall development. While the body prioritises energy supply to so-called central organs, mitochondrial activity in other tissues declines with age.
In reproductive biology, mitochondria play a critical role in:
oocyte maturation
fertilisation
early embryo development
The oocyte is one of the most energy-demanding cells in the human body, containing a mitochondrial content comparable to that of the brain or liver. Adequate mitochondrial function is therefore essential for successful fertilisation and embryo development.
An oocyte consists of:
the nuclear genetic material (contained within the spindle)
the surrounding cytoplasm
mitochondria, which contain their own circular DNA
Mitochondrial DNA consists of 37 genes responsible for encoding proteins involved in cellular respiration and energy production. Importantly, not all mitochondrial disorders originate from mitochondrial DNA; some are caused by mutations in nuclear DNA that affect mitochondrial function.
Dr Dorofeyeva emphasised that mitochondrial DNA is inherited almost exclusively from the mother. While sperm contain mitochondria in the tail, these are not functionally transmitted after fertilisation.
Two broad categories of mitochondrial dysfunction were discussed.
Primary mitochondrial disorders are genetic conditions inherited through mitochondrial or nuclear DNA. These disorders may affect multiple organs and systems and often have no effective treatment. Symptoms can appear at birth or later in life, making prediction difficult. For patients carrying these mutations, MRT offers a way to prevent transmission to offspring.
Secondary mitochondrial dysfunction refers to an age-related or acquired decline in mitochondrial function. This is particularly relevant in fertility treatment, where reduced mitochondrial activity contributes to poor oocyte quality, lower fertilisation rates, and increased aneuploidy with advancing maternal age.
As women age, oocyte quality declines due to:
reduced mitochondrial activity
increased oxidative stress
impaired DNA repair mechanisms
changes in granulosa and theca cell function
Dr Dorofeyeva described how ovarian tissue from older patients shows:
reduced granulosa cell numbers
increased apoptosis
decreased follicular responsiveness
These changes explain why empty follicles, immature oocytes, and failed embryo development become more common with age, even when ovarian stimulation appears adequate.
Currently, there is no direct clinical test to measure mitochondrial activity in oocytes.
Dr Dorofeyeva explained that while genomic, transcriptomic, and metabolomic tools exist, they have limitations in sensitivity and specificity. Biomarkers such as lactate and pyruvate are under investigation, but reliable clinical measurement remains an unmet need.
For donors, mitochondrial quality is assessed indirectly by reviewing previous donation outcomes, including fertilisation rates, blastocyst formation, and pregnancy results.
MRT does not involve gene editing, cloning, or DNA modification. Instead, it reconstructs the oocyte or zygote by transferring nuclear genetic material from the intended mother into a donor cell with healthy cytoplasm and mitochondria.
The goal is to provide the mother’s nuclear DNA with a younger, healthier cellular environment capable of supporting normal development.
Dr Dorofeyeva described two clinically relevant MRT techniques.
Maternal Spindle Transfer (MST)
This technique is performed at the oocyte stage, before fertilisation. The spindle containing the maternal nuclear DNA is removed and transferred into an enucleated donor oocyte. The reconstructed oocyte is then fertilised.
MST requires specialised equipment, including polarised light microscopy, to visualise the spindle. Not all oocytes have a visible spindle, and the technique is highly operator-dependent.
Pronuclear Transfer (PNT)
PNT is performed after fertilisation, at the zygote stage. Both the patient’s and donor’s oocytes are fertilised. The pronuclei containing parental DNA are removed from the patient’s zygote and transferred into the donor zygote after removal of its pronuclei.
PNT is technically less complex because pronuclei are easier to visualise and manipulate.
Successful MRT depends heavily on donor oocyte quality.
Dr Dorofeyeva explained that donors are selected based on:
proven fertility (having their own child)
excellent previous embryological outcomes
high blastocyst and euploid rates
fresh oocyte availability
Morphology alone is insufficient; some donors with average-looking oocytes produce superior blastocyst outcomes, highlighting the importance of functional performance rather than appearance.
After reconstruction, embryos are cultured to the blastocyst stage. Dr Dorofeyeva strongly recommended preimplantation genetic testing (PGT-A) for all MRT embryos.
MRT does not correct existing nuclear DNA abnormalities. Its role is to optimise the cellular environment, potentially allowing normal DNA repair mechanisms and reducing mosaicism. However, chromosomal abnormalities can still occur and must be screened.
One important observation shared was the low incidence of mosaic embryos following MRT. While data are still being prepared for publication, Dr Dorofeyeva suggested that improved cytoplasmic environment may support embryonic self-correction mechanisms.
However, she stressed that MRT cannot repair significant nuclear DNA mutations. If a major genetic error is present, embryo development will still arrest.
MRT is legally permitted in a limited number of countries.
The United Kingdom approved MRT in 2015 following extensive ethical review. Australia passed legislation in 2022, although clinical cases are still pending. In many countries, MRT remains restricted, requiring cross-border treatment.
Ethical discussions consider:
donor anonymity
long-term follow-up of children
parental rights
transparency and patient education
Dr Dorofeyeva compared MRT’s ethical trajectory to that of IVF itself, noting that many now-routine treatments were once considered controversial.
Beyond reproductive medicine, mitochondrial therapies are being explored for:
neurodegenerative diseases
metabolic disorders
age-related conditions
cancer research
Although still experimental, these developments highlight the central role of mitochondria in human health and disease.
Dr Dorofeyeva concluded that:
MRT prevents transmission of mitochondrial genetic disorders
it may offer solutions for secondary mitochondrial dysfunction
success depends on advanced laboratory expertise and donor selection
genetic testing remains essential
ongoing research and standardisation are crucial
patient education is fundamental for informed decision-making
MRT is not a universal solution, but for selected patients, it represents a meaningful and scientifically grounded option.
This is the most common question, I believe, and I totally understand and support the fact that we need to try to answer this question frankly. Speaking honestly, I’m not sure that I will be able to answer it fully because, as I mentioned, the first baby we know of was born using this technique in 2016. Our first baby in our group — treatment performed in Ukraine — was born in 2017. Since that time, we have 29 babies born in our group. We are in touch with the majority of the parents, though not with all of them — some were not happy to continue. You know, this is a very voluntary process, I would say.
But the majority of patients are providing information about the health status of their babies. We created newborn assessment forms and are collecting them. However, the oldest baby is still 11 now, so we need to understand that this is not yet a long-term perspective. We need to consider this and treat it as a responsibility. So far, there is no physical, mental, or any other type of development issue different for those babies born specifically in our group.
And you need to know that I think this is a bit underreported. I personally believe that there are more babies globally — just not every team working on these shares their statistics.
The total number of transfers was over 70. We need to understand that when we calculated those 29, we still had many ongoing pregnancies, so we were not calculating those separately. For the period, we have the latest statistics as 56% of clinical pregnancies for the whole population. Our population is between 39 and 52 years old — those who are accumulating their eggs. The oldest woman who gave birth was 48. For those between 48 and 52, we don’t have live births yet, but it’s still possible. This is very individual.
If you had asked me 5 years ago — because I’ve been consulting patients since 2008 — the majority of my patients were egg donation patients due to my dedication to third-party reproduction. When I learned about this technology, I truly believed that patients need to know about this opportunity and just select the path they would like to proceed with. One way is to continuously do IVF with obviously very low potential to succeed — this is an emotional burden, financial cost, and a waste of time, in my view. Egg donation is an option, but we just discussed what the difference is.
Mitochondrial replacement therapy is an innovative approach that merges both your own IVF and the fact that you have a genetically related baby. The only real, frankly speaking, question is the long-term issues. But through the technique, the technology, and the process as we know it is performed, we do not expect any potential risks. It’s just like how the most common question used to be whether Louise Brown would be fertile and able to have children on her own — and now we have that answer.
We need a bit more time.
Yes, so we are happy to evaluate every situation separately. Something very important to say here is that age is important — but it’s not the most important factor. Something else is also important. Ideally, we would evaluate this all in 1 age, the fact if the patient is still cycling.
If she is still cycling, this is a positive, predictable parameter. If she is not cycling, then we need to understand how long ago she stopped cycling. Then, of course, we would need the hormones — AMH level and the dynamics of the AMH level. That would be ideal. Meaning: What is the AMH today, and what was the AMH before — how long ago did you measure it?
If it was last month, share it with us. If that was three months or half a year ago — share the previous AMH too. So, we understand the decline and at which stage of the potential premenopause or menopause you are. If you are already in menopause, then we also evaluate how long ago the last cycle, what’s going on at the hormonal level, at the hypothalamic level.
Then AMH, FSH as well, and the dynamics of the FSH will be helpful. Then, antral follicle number or pelvic scan details — taking into account the volume of the ovaries, not only measuring if the follicles are there but also the structure and the volume. If the follicles are there or not. All of these parameters are something we would need to evaluate before providing an individual answer.
Every patient is different — it can be very, very different. As I said, I would be happy to treat only patients who are cycling regularly and who have relatively high or reasonable AMH, but it’s not always the case. Collaboration is important — it’s important to understand the facts and to accept them.
in our protocol, we are using mature oocytes for the technology. We start the process once we have a mature oocyte or the already-created zygote.
If we are getting MIs or GV oocytes, we are maturating them, so the process will continue after they reach the mature stage of development. We know that there is a group that suggests that you specifically need to retrieve GV-stage oocytes. We are not in direct communication with them, so we cannot ask the questions we want to ask, unfortunately—specifically how we see and evaluate the difference and potential risks through the transfer on the state of the germinal vesicle.
But we are not saying this is wrong—just that we cannot evaluate it. We are saying: this is our protocol, and this is our technique, which we know how it works. If that group will be able to publish their data and we will be able to discuss or evaluate, it will be just great. So maybe this is also something that works.
We had different cases, and based on our statistical results, we believe that starting with four zygotes—not oocytes but zygotes—is something very optimal, where we already expect to receive at least one euploid blastocyst.
For the technique in general, we include up to 15 oocytes as a maximum—this is our current, let’s say, approach. For many, many patients, we don’t need 15 because this is too hard to accumulate that number. For some specific patients, if that’s possible, of course, it’s a choice of the patient—but it’s a good number to start with four. Also, we had cases starting with one egg and a healthy euploid embryo successfully implanted—and the lady is pregnant now in the third trimester.
But this is more like a clinical case, not statistics. I remember also a case where we couldn’t reach more than two—we had two eggs, one euploid transferred, not successful. However, the patient decided also in parallel with MST or PNT, they did an egg donation. So, they fertilized four eggs from the donor, and we also received two euploid blastocysts from the donor. She is now pregnant with the donor embryo. She tried—it was not an option. It unfortunately didn’t work with the first embryo transfer, but she is still successfully pregnant.
So here, it’s about acceptance of the next steps, let’s say.
The majority of the statistical data, and something that we do—the majority of cases are PNT (Pronuclear Transfer) cases, just because of the accumulation of the zygotes. Quite often, they are frozen somewhere else, not in our facility, and then sent over—so the zygote is a more stable structure. The majority of the cases would be PNT cases.
From those MST cases, the MST statistics are not significantly different. We can say that there is no statistically significant difference between MST and PNT.
No, there is no waiting list, because we understand that we are working with advanced maternal age patients where we never suggest to wait. If you want to start stimulation, you can start it when the conditions are ready for this.
We are happy to evaluate your stimulation if you are starting this at home, or if you want to be supervised by our team, you can always just come to Tiana, and there is a clinic which can monitor you there. It’s busy, but it’s not crazy busy, so we’re always accepting new patients—any time.
It’s a very individual question, because we are having many accumulated cycles, as I said, with our patients. For many patients who are starting with us, it’s not the first cycle, so there are already some learning points from their previous stimulation outcomes.
To simply answer your question, I would say it’s between 17 and 20. This is when we would trigger the patient. It will also depend on very, very different factors, like what would be the estradiol level, how long this follicle reached this size— either that was very rapid development, which is more than 3 millimetres per day, or it was a very slow development, which is less than 1 millimetre per day.
The decision point here will be very different. What were the previous outcomes based on the length of stimulation, type of the trigger, time (how long this follicle was developing for, and level of the estradiol? If we can get this, we of course will evaluate and then we’ll make an individual decision for this specific patient on when to trigger.
If you’re talking about technical barriers — because as I would say, they are not technical. It’s a global regulation and the acceptance of innovation. I would not call this technical, it’s more like a global perspective.
But if specifically the question is about technical: it’s just that unfortunately (or fortunately), it’s a very operator-dependent technique. Not every embryologist has the skills. This is something we either can do excellently — those micromanipulations — or we cannot. I believe this is very personal knowledge or practice, which not everyone is given.
Another barrier is in the protocol. Actually, one protocol was published, and I know that many embryologists are trying to follow it, but it doesn’t work well. There is an adaptation of the protocol in order to achieve the best results — and then the groups are not sharing that protocol, because there is no general policy for this technique. That’s why these are probably technical limitations. Equipment — that is something that can be solved, of course — but this is quite specific as well.
This is per transfer, not per patient. Yes, we had several patients who had multiple births. We have two — and a third family — two families already which had twins. One more family will also have a new child very soon. Three patients out of all these numbers had repetitive transfers — but repetitive successful ones.
We’ve had repetitive unsuccessful ones in that group as well.
Usually, if the patient accepts the fact that donor embryos need to be selected, we give the option to choose a donor — or share with the patient the phenotypical criteria of the donors who are going to be used in this technique. We are matching donors with blood groups, so this is something that will still be matched.
We do not match them with phenotypical characteristics if we know that oocyte donation is not going to be a treatment option here because phenotypical characteristics are not inherited through mitochondrial DNA. The nuclear DNA is responsible for how the baby looks. If we know that oocyte donation will be a treatment option, we share the phenotypical characteristics. However, donors are specifically selected, so there will be a very limited number of donors to choose from because these are proven donors selected by the medical and lab team for this technique — but not based on how they look.
We also did this before: we used an MRT donor for mitochondrial replacement purposes and separately fertilized donor oocytes from a specific donor with specific phenotypical characteristics chosen by the patient. This is also possible.
It is correct. Neither of the techniques will increase the euploidy rate — because it works totally differently. It creates the environment to increase the chance of getting a euploid embryo. If you get a euploid embryo, it will have the highest chance possible for implantation.
For example, we don’t have many surrogacy cases, but it’s also possible to proceed with surrogacy treatment using MRT techniques because the embryo is genetically related to the parents. Even if that’s a specific requirement that is needed. Sometimes we just do not have proper implantation conditions for patients of advanced maternal age. Implantation potential depends on the environment of the uterus and the quality of the embryo. Of the 6 transfers that we did to surrogates, 5 are clinically pregnant and carrying babies, and 2 have already been born.
It’s a very high implantation potential, and we are talking about the most appropriate condition, choosing the surrogate mum. It’s never 100% — we wish it would be and that all 6 would be successful, because these are very important embryos for us. As I said, we take care of every pregnancy.
We take care of the technology itself, and we take care of our patients — even if you’re our patient without MRT, we will do our best with transfer and egg retrieval, and so on. Today, we are talking about this technique.
Transferring the spindle from the environment of an advanced maternal oocyte — if we reconstruct this oocyte and put the spindle into a young and healthy environment — then, based on the statistics we have, we increase the euploidy rate. We are currently seeing an average euploidy rate of 64%.
We will be able to distribute this between the age groups. I know this is a very common question — you ask: What about specifically age 47? What about 45+? What about 50+? What if this is 42 to 43? But the numbers — we do not have huge numbers.
If we divided this into such small age groups, the variation would be very, very high. this would be a bias of small numbers. That’s why we are presenting the data grouped.
