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Review
. 2020 Nov 3;20(1):53-61.
doi: 10.1002/rmb2.12356. eCollection 2021 Jan.

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

Mitsutoshi Yamada  1 , Suguru Sato  1 , Reina Ooka  1 , Kazuhiro Akashi  1 , Akihiro Nakamura  1   2 , Kenji Miyado  2 , Hidenori Akutsu  2 , Mamoru Tanaka  1
Affiliations
Review

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

Mitsutoshi Yamada et al. Reprod Med Biol. .

Abstract

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.

Keywords: mitochondrial DNA; mitochondrial DNA carryover; mitochondrial disease; mitochondrial replacement; mtDNA genetic drift.

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Conflict of interest statement

Conflict of interest: The authors declare that they have no conflicts of interest. Human/animal rights: This article does not contain any studies with human and animal participants performed by any of the authors.

Figures

Figure 1
Figure 1
Spindle transfer for mitochondria replacement. Spindles are enucleated from both oocytes, and the carrier's spindle (orange) is fused with the enucleated healthy donor oocyte (blue). After nuclear exchange, the resulting oocyte, which consists of nuclear DNA from the carrier and cytoplasm from the donor oocyte, is subjected to in vitro fertilization (IVF) with the partner's sperm
Figure 2
Figure 2
Overview of specified embryos defined by the Act on Regulation of Human Cloning Techniques. Embryos produced by genome transfer techniques are categorized as “Specified Embryos” in the Act on Regulation of Human Cloning Techniques. No person shall transfer a human somatic cell nuclear transfer (SCNT) embryo, human‐animal hybrid embryo, human‐animal clone embryo, or human‐animal chimeric embryo into a human or animal uterus. The image was adapted from the Announcement of Ministry of Education, Culture, Sports, Science and Technology‐Japan 50
See this image and copyright information in PMC

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