Mitochondrial replacement by genome transfer in human oocytes: Efficacy, concerns, and legality

• Published in: Reproductive medicine and biology 2021-01, Vol.20 (1), p.53-61
• Main Authors: Yamada, Mitsutoshi, Sato, Suguru, Ooka, Reina, Akashi, Kazuhiro, Nakamura, Akihiro, Miyado, Kenji, Akutsu, Hidenori, Tanaka, Mamoru
• Format: Article
• Language: English
• Subjects: Analysis; Cell division; Cell lines; Cytoplasm; Deoxyribonucleic acid; Disease; DNA; Electron transport; Embryos; Gene mutations; Genetic aspects; Genetic disorders; Genetic drift; Genetic research; Genomes; Genomics; Genotypes; Heteroplasmy; Mini Review; Mini Reviews; Mitochondria; mitochondrial disease; Mitochondrial DNA; mitochondrial DNA carryover; mitochondrial replacement; mtDNA genetic drift; Mutation; Oocytes; Proteins; Stem cells
• ISSN: 1445-5781; 1447-0578
• DOI: 10.1002/rmb2.12356

Background Pathogenic mitochondrial (mt)DNA mutations, which often cause life‐threatening disorders, are maternally inherited via the cytoplasm of oocytes. Mitochondrial replacement therapy (MRT) is expected to prevent second‐generation transmission of mtDNA mutations. However, MRT may affect the function of respiratory chain complexes comprised of both nuclear and mitochondrial proteins. Methods Based on the literature and current regulatory guidelines (especially in Japan), we analyzed and reviewed the recent developments in human models of MRT. Main findings MRT does not compromise pre‐implantation development or stem cell isolation. Mitochondrial function in stem cells after MRT is also normal. Although mtDNA carryover is usually less than 0.5%, even low levels of heteroplasmy can affect the stability of the mtDNA genotype, and directional or stochastic mtDNA drift occurs in a subset of stem cell lines (mtDNA genetic drift). MRT could prevent serious genetic disorders from being passed on to the offspring. However, it should be noted that this technique currently poses significant risks for use in embryos designed for implantation. Conclusion The maternal genome is fundamentally compatible with different mitochondrial genotypes, and vertical inheritance is not required for normal mitochondrial function. Unresolved questions regarding mtDNA genetic drift can be addressed by basic research using MRT. This review discusses current approaches and legality regarding mitochondrial replacement for preventing the inheritance of mitochondrial diseases such as encephalomyopathy, cardiomyopathy, hearing loss, diabetes, and renal impairment, caused by pathogenic mutations in mtDNA. Although relevant advances have been achieved in the field of treatments for preventing mutant mtDNA transmission, some concerns and challenges remain such as mtDNA carryover, mtDNA genetic drift, and donor‐recipient compatibility.