The need to understand the underlying mechanisms associated with mitochondrial therapies in assisted reproduction before further clinical trials are performed

Over a number of years, there has been growing interest in the introduction of more invasive ARTs, such as nuclear transfer, otherwise referred to as mitochondrial donation, and mitochondrial supplementation/transfer into clinical medicine. They have been proposed to overcome repeated failed fertilization or developmental arrest or to prevent carriers of mitochondrial DNA disease from having affected children. These technologies require considerable manipulation of the oocyte, which can affect its epigenetic programming that was established as it grew and developed into a fertilizable oocyte. Consequently, when a nucleus is transferred into an enucleated oocyte or pronuclei are transferred into an enucleated zygote, the nucleus must adapt to its new cytoplasmic environment in readiness for the waves of DNA demethylation and methylation that take place during preimplantation development. As a result, some key developmental gene networks are affected. Additionally, these approaches also affect patterns of mitochondrial DNA inheritance, with some embryos and offspring possessing mitochondrial DNA carried over into the oocyte with the nucleus, as well as the mitochondrial DNA from the donor oocyte. Similar outcomes result from the addition of extra mitochondrial DNA into oocytes through mitochondrial supplementation. We provide a background as to how these technologies evolved and discuss recent outcomes associated with clinical work so far undertaken within these approaches and their consequences for the offspring. We conclude that these technologies are not simply replacing or replenishing defective ooplasms with new or extra mitochondria but rather induce a series of genomic and epigenomic events that we do not yet fully understand. To our minds, these issues should be first addressed before clinical trials are continued.