Potential of Mitochondrial Genome Editing for Human Fertility Health.

Lin Fu,Yu-Xin Luo,Hui Liu,Yang Yu,Hong-Zhen Li,Ying Liu

doi:10.3389/fgene.2021.673951

Abstract

Mitochondrial DNA (mtDNA) encodes vital proteins and RNAs for the normal functioning of the mitochondria. Mutations in mtDNA leading to mitochondrial dysfunction are relevant to a large spectrum of diseases, including fertility disorders. Since mtDNA undergoes rather complex processes during gametogenesis and fertilization, clarification of the changes and functions of mtDNA and its essential impact on gamete quality and fertility during this process is of great significance. Thanks to the emergence and rapid development of gene editing technology, breakthroughs have been made in mitochondrial genome editing (MGE), offering great potential for the treatment of mtDNA-related diseases. In this review, we summarize the features of mitochondria and their unique genome, emphasizing their inheritance patterns; illustrate the role of mtDNA in gametogenesis and fertilization; and discuss potential therapies based on MGE as well as the outlook in this field.

Highlights

Introduction of the Mitochondria and Mitochondrial DNA (mtDNA)Mitochondria are double-membrane organelles producing more than 90% of adenosine triphosphate (ATP) through oxidative phosphorylation (OXPHOS)
There are two main strategies for targeting mitochondria to improve fertility: One is to enhance mitochondrial quality, which mainly includes the use of pharmacologic agents capable of protecting against oxidative stress or increasing the overall efficiency of energy production and calorie restriction (Cecchino et al, 2018); the other is cytoplasmic and mitochondrial transfer therapy developed to prevent the transmission of severe hereditary mitochondrial diseases caused by pathogenic mutations of mtDNA (Adashi and Cohen, 2018)
Gammage et al (2014) reported progress in their findings on the use of zinc finger nucleases (ZFN) to target and cleave predetermined loci in mtDNA (Gammage et al, 2014). They generated a mitochondrially targeted ZFN carrying two cleavage domains bound to the same protein that selectively eliminates the deleterious mtDNA, as well as a mtDNA region most frequently associated with diseases, which contains several transfer RNAs and structural genes of the OXPHOS apparatus (Gammage et al, 2014)

Summary

Introduction

Introduction of the Mitochondria and mtDNAMitochondria are double-membrane organelles producing more than 90% of adenosine triphosphate (ATP) through oxidative phosphorylation (OXPHOS). Mitochondrial genome editing refers to modification of human zygotes or oocytes at risk for mtDNA disease via the intracytoplasmic microinjection of mitochondria-targeted nucleases in order to preclude the germline transmission of mutant mtDNA haplotypes.

Results

Conclusion