(A) Cartoon of the mitochondrial bottleneck: heteroplasmy of mtDNA in primordial germ cells may segregate during the ∼50-fold increase in mtDNA content as they develop into primary oocytes, resulting in different mutant loads (0–80% in this illustration). Although a major component of the trans-generation switching in mutant load has occurred by the oocyte stage, further segregation occurs during embryonic and fetal life. Three available ways to reduce the risk of transmitting mitochondrial DNA disease: oocyte donation, pre-implantation genetic diagnosis and mitochondrial replacement therapy. Red represents mutant mitochondrial DNA, pink and white represent successively higher proportions of normal mitochondrial DNA. Blue represents genetic material from an unrelated donor. (B) No intervention: offspring's mutant mitochondrial DNA load will vary greatly. (C) Oocyte donation: current availability in the United Kingdom is limited by the availability of oocyte donors. (D) Pre-implantation genetic diagnosis: is available in the United Kingdom for most mitochondrial DNA diseases. (E) MRT nuclear transfer: being developed in the United Kingdom, first cases likely this year, not yet available in the United States.