The role of mtDNA in oocyte quality and embryo development

Abstract

The mitochondrial genome resides in the mitochondria present in nearly all cell types. The porcine (Sus scrofa) mitochondrial genome is circa 16.7 kb in size and exists in the multimeric format in cells. Individual cell types have different numbers of mitochondrial DNA (mtDNA) copy number based on their requirements for ATP produced by oxidative phosphorylation. The oocyte has the largest number of mtDNA of any cell type. During oogenesis, the oocyte sets mtDNA copy number in order that sufficient copies are available to support subsequent developmental events. It also initiates a program of epigenetic patterning that regulates, for example, DNA methylation levels of the nuclear genome. Once fertilized, the nuclear and mitochondrial genomes establish synchrony to ensure that the embryo and fetus can complete each developmental milestone. However, altering the oocyte's mtDNA copy number by mitochondrial supplementation can affect the programming and gene expression profiles of the developing embryo and, in oocytes deficient of mtDNA, it appears to have a positive impact on the embryo development rates and gene expression profiles. Furthermore, mtDNA haplotypes, which define common maternal origins, appear to affect developmental outcomes and certain reproductive traits. Nevertheless, the manipulation of the mitochondrial content of an oocyte might have a developmental advantage.

Mitochondrial DNA Supplementation of Oocytes Has Downstream Effects on the Transcriptional Profiles of Sus scrofa Adult Tissues with High mtDNA Copy Number

“…We have shown that supplemented heterologous mtDNA was detectable in tail samples from piglets and adult tissues (brain, calf muscle and heart), and levels of supplemented heterologous mtDNA varied amongst pigs and tissues but were at consistently low levels [29]. Heteroplasmy causes alterations in OXPHOS activity and mitochondrial ROS levels [22], which, in turn, modulate several signalling pathways, including RIG-I-like receptor (RLR) innate immune signalling [38,41]. Indeed, it has also been proposed that inherited mtDNA SNPs and somatic mutations could influence inflammatory pathways by imparting functional changes in mitochondria [38].…”

“…These processes could explain the changes in expression in inflammatory response pathway genes in blastocysts [20,28]. Heteroplasmy (in this case the presence of two distinct mitochondrial genomes [22]) following heterologous third-party mtDNA supplementation could be one of the possible causes, especially given that the immune response may recognise this population of mtDNA as 'foreign' rather than 'self' mtDNA [40]. We have shown that supplemented heterologous mtDNA was detectable in tail samples from piglets and adult tissues (brain, calf muscle and heart), and levels of supplemented heterologous mtDNA varied amongst pigs and tissues but were at consistently low levels [29].…”

“…Ooplasmic transfer and mitochondrial supplementation of oocytes have been shown to improve rates of fertilisation and development of mammalian embryos [15,[20][21][22][23][24]. Furthermore, supplementation in combination with intracytoplasmic sperm injection (ICSI) of mtDNA-deficient pig oocytes triggers a mtDNA replication event by the two-cell stage of embryo development that increases mtDNA content by 4.4-fold and improves embryo quality and developmental rates [20].…”

Aging-Related Ovarian Failure and Infertility: Melatonin to the Rescue

“…The molecular mechanisms for follicle growth and oocyte maturation involve the signaling molecules mammalian target of rapamycin (mTOR) and AKT (protein kinase B) as the initiators of these processes [ 109 ]. During the reproductive life span, in broad terms, fertility generally correlates with the residual quantity of oocytes remaining in the ovaries (the ovarian reserve) [ 110 ] although a successful pregnancy also depends on the availability of high-quality oocytes [ 111 ]. Typically, the loss of fertility for women becomes apparent during the fourth decade of life ( Figure 2 ).…”

Mitochondrial DNA Deficiency and Supplementation in Sus scrofa Oocytes Influence Transcriptome Profiles in Oocytes and Blastocysts

“…The supplementation of oocytes at the time of fertilisation with mtDNA, packaged within mitochondria derived from sister oocytes, has shown to improve the rates of the fertilisation and development of mammalian embryos [ 13 , 14 , 17 , 18 ]. This process adds approximately an extra 800 copies of mtDNA [ 13 ], which represents 0.3% of the fertilisable oocyte’s total mtDNA content (~300,000).…”