Mitochondrial replacement therapy (MRT), sometimes called mitochondrial donation, is the replacement of mitochondria in one or more cells to prevent or ameliorate disease. MRT originated as a special form of in vitro fertilisation in which some or all of the future baby's mitochondrial DNA (mtDNA) comes from a third party. This technique is used in cases when mothers carry genes for mitochondrial diseases. The therapy is approved for use in the United Kingdom Index page with links to summaries including one page summary flyer. and Australia. Eight babies have been born using MRT in the UK as of July 2025. A second application is to use autologous mitochondria to replace mitochondria in damaged tissue to restore the tissue to a functional state. This has been used in clinical research in the United States to treat cardiac-compromised newborns.
Medical uses
In vitro fertilisation Mitochondrial replacement therapy has been used to prevent the transmission of mitochondrial diseases from mother to child. In the UK it could only be performed in clinics licensed by the Human Fertilisation and Embryology Authority (HFEA), only for people individually approved by the HFEA, for whom preimplantation genetic diagnosis is unlikely to be helpful, and only with informed consent given that the risks and benefits are not well understood. Linked in HFEA announcement of the regulations issued 15 December 2016.
Relevant mutations are found in about 0.5% of the population. Disease affects a much smaller proportion of the population around one in 5000 individuals, 0.02% because cells contain many mitochondria and only some carry mutations. The proportion of the cell's mitochondria affected needs to reach a threshold in order to affect the entire cell; and many cells need to be affected for the person to show disease.
The average number of births per year among women at risk for transmitting mtDNA disease is estimated as approximately 150 in the United Kingdom and 800 in the United States.
Where both legal and feasible, MRT provides a fourth reproductive option for women who are at risk for transmitting mtDNA disease and who want to prevent transmission. The other three are using an egg from another woman, adoption, or childlessness.
Tissue function Autologous mitochondria extracted from healthy tissue and supplied to damaged tissue has been used to treat cardiac-compromised newborns. Alternatives to the approach include use of an extracorporeal membrane oxygenator (ECMO) or tissue or organ transplantation.
Techniques In vitro fertilization involves removing eggs from a woman, collecting sperm from a man, fertilizing the egg with the sperm, allowing the fertilized egg to form a blastocyst, and then transferring the blastocyst into the uterus. MRT involves an additional egg from a third person, and manipulation of both the recipient egg and the donor egg.
As of 2016 there were three MRT techniques in use: maternal spindle transfer (MST); pronuclear transfer (PNT); and the newest technique, polar body transfer (PBT). The original technique, cytoplastic transfer, in which mitochondria-containing cytoplasm taken from a donor egg is simply injected into the recipient egg, is no longer used. The UK Parliament only approved the use of two techniques -maternal spindle transfer and pronuclear transfer - for mitichondrial replacement in 2015.
Maternal spindle transfer
In maternal spindle transfer, an oocyte is removed from the recipient, and when it is in the metaphase II stage of cell division, the spindle-chromosome complex is removed; some of the cytoplasm comes with it, so some mitochondria are likely to be included. The spindle-chromosome complex is inserted into a donor oocyte from which the nucleus has already been removed. This egg is fertilized with sperm and allowed to form a blastocyst, which can then be investigated with preimplantation genetic diagnosis to check for mitochondrial mutations, prior to being implanted in the recipient's uterus.
Pronuclear transfer In pronuclear transfer, an oocyte is removed from the recipient and fertilized with sperm. The donor oocyte is fertilized with sperm from the same person. The male and female pronuclei are removed from each fertilized egg prior to their fusing, and the pronuclei from the recipient's fertilized egg are inserted into the fertilized egg from the donor. As with MST, a small amount of cytoplasm from the recipient egg may be transferred, and as with MST, the fertilized egg is allowed to form a blastocyst, which can then be investigated with preimplantation genetic diagnosis to check for mitochondrial mutations before being implanted in the recipient's uterus.
Polar body transfer
In polar body transfer, a polar body (a small cell with very little cytoplasm that is created when an egg cell divides) from the recipient is used in its entirety, instead of using nuclear material extracted from the recipient's normal egg; this can be used in either MST or PNT. This technique was first published in 2014 and as of 2015 it had not been consistently replicated, but is considered promising as there is a greatly reduced chance for transmitting mitochondria from the recipient because polar bodies contain very few mitochondria, and it does not involve extracting material from the recipient's egg.
Cytoplasmic transfer Cytoplasmic transfer was originally developed in the 1980s in the course of basic research conducted with mice to study the role that parts of the cell outside of the nucleus played in embryonic development. In this technique, cytoplasm, including proteins, messenger RNA (mRNA), mitochondria and other organelles, is taken from a donor egg and injected into the recipient egg, resulting in a mixture of mitochondrial genetic material. This technique started to be used in the late 1990s to "boost" the eggs of older women who were having problems conceiving and led to the birth of about 30 babies. Concerns were raised that the mixture of genetic material and proteins could cause problems with respect to epigenetic clashes, or differences in the ability of the recipient and donor materials to effect the development process, or due to the injection of the donor material. After three children born through the technique were found to have developmental disorders (two cases of Turner's syndrome and one case of pervasive developmental disorder (an autism spectrum disorder), the FDA banned the procedure until a clinical trial could prove its safety. As of 2015 that study had not been conducted, but the procedure was in use in other countries.
A related approach uses autologous mitochondria taken from healthy tissue to replace the mitochondria in damaged tissue. Transfer techniques include direct injection into damaged tissue and injection into vessels that supply blood to the tissue.
Risks Assisted reproduction via MRT involves preimplantation genetic screening of the mother, preimplantation genetic diagnosis after the egg is fertilized, and in vitro fertilization. It has all the risks of those procedures.
In addition, both procedures used in MRT entail their own risks. On one level, the procedures physically disrupt two oocytes, removing nuclear genetic material from the recipient egg or fertilized egg and inserting the nuclear genetic material into the donor unfertilized or fertilized egg; the manipulations for both procedures may cause various forms of damage that were not well understood as of 2016.
Maternal mitochondria will be carried over to the donor egg; as of 2016 it was estimated that using techniques current in the UK, maternal mitochondria will comprise only around 2% or less of mitochondria in the resulting egg, a level that was considered safe by the HFEA and within the limits of mitochondrial variation that most people have.
Because MRT procedures involve actions at precise times during egg development and fertilization, and involves manipulating eggs, there is a risk that eggs may mature abnormally or that fertilization may happen abnormally; as of 2016 the HFEA judged that laboratory techniques in the UK had been well enough developed to manage these risks to proceed cautiously with making MRT available.
Because mitochondria in the final egg will come from a third party, different from the two parties whose DNA is in the nucleus, and because nuclear DNA encodes genes that make some of the proteins and mRNA used by mitochondria, there is a theoretical risk of adverse "mito–nuclear" interactions. While this theoretical risk could possibly be managed by attempting to match the haplotype of the donor and the recipient, as of 2016 there was no evidence that this is an actual risk.
Because MRT is a relatively new technology, there are concerns that it is not yet safe for public use as there have been limited studies that used MRT in large animal models.
Finally, there is a risk of epigenetic modification to DNA in the nucleus and mitochondria, caused by the procedure itself or by mito–nuclear interactions. As of 2016 these risks appeared to be minimal but were being monitored by long-term study of children born from the procedure.
History In the United States in 1996 embryologist Jacques Cohen and others at the Institute for Reproductive Medicine and Science, Saint Barnabas Medical Center in Livingston, New Jersey first used cytoplasmic transfer in a human assisted reproduction procedure.Kim Tingley for the New York Times. June 27, 2014 The Brave New World of Three-Parent I.V.F. In 1997 the first baby was born using this procedure. In 2001, Cohen and others reported that ten single babies, twins, and a quadruplet at his New Jersey clinic and a further six children in Israel had been born using his technique. Using modifications of his procedure, a baby had been born at Eastern Virginia Medical School, five children at the Lee Women's Hospital Infertility Clinic in Taichung, Taiwan. twins in Naples, Italy and a twins in India. In total as of 2016, 30–50 children worldwide had been reported to have been born using cytoplasmic transfer.
In 2002, the US Food and Drug Administration (FDA) asked a Biological Response Modifiers Advisory Committee Meeting to advise on the technique of cytoplasmic transfer to treat infertility. This committee felt that there were risks at the time of inadvertent transfer of chromosomes and enhanced survival of abnormal embryos. The FDA informed clinics that they considered the cytoplasmic transfer technique as a new treatment, and, as such, it would require an Investigational New Drug (IND) application. Cohen's clinic started the pre-IND application, but the clinic then went private, funding for the application dried up, the application was abandoned, the research team disbanded, and the cytoplasmic transfer procedure fell out of favor. In 2016, 12 (out of the 13) parents of children born using cytoplasmic transfer at the Saint Barnabas Center participated in a limited follow-up inquiry via online questionnaire. Children whose ages then were 13–18 reported no major problems.
In 2009, a team in Japan published studies of mitochondrial donation. In the same year, a team led by scientists at Oregon Health & Science University published results of mitochondrial donation in monkeys; that team published an update reporting on the health of the monkeys born with the technique, as well as further work it had done on human embryos.