Human oocytes have an abundance of mitochondria that have their own genome. Mitochondrial<br />
functions are exerted through evolutionarily-developed interactions between the nucleus and<br />
mitochondria. Since 1996, fertility clinics have practiced various types of germline mitochondrial<br />
DNA (mtDNA) modification that alter the composition of mtDNA copies in oocytes or zygotes using<br />
micromanipulation. Experimental reproductive medicine has primarily intended to treat intractable<br />
infertility and has been used to prevent the maternal transmission of a pathogenic mtDNA mutation<br />
to offspring. In some cases, it has helped parents have a healthy genetically-related child; in others,<br />
it has resulted in miscarriages, aneuploid fetuses, or developmental disorders in the offspring.<br />
Adverse events have raised ethical controversy, leading to restrictive or prohibitive policies in<br />
the USA and China. Conversely, the UK recently became the first nation to explicitly permit two<br />
types of germline mtDNA modification (termed mitochondrial donation) for the sole purpose<br />
of preventing serious mitochondrial disease in offspring. The aim of this review is three-fold:<br />
first, to reshape the medical concept and evolution of germline mtDNA modification, while<br />
revisiting 14 clinical cases. Second, to analyse the legality of mtDNA modification, focussing on<br />
16 Western countries. Finally, to consider the ethical aspects, including permissible cases,<br />
reproductive options, use of preimplantation and prenatal testing, and the humane follow-up<br />
of resultant children. The clinical use of germline mtDNA modification will likely become legal,<br />
at least for use in preventative medicine, in some countries. However, the potential clinical, ethical,<br />
and evolutionary implications mean that caution is required when considering its wider application.