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Review
. 2023 Jul;90(7):621-633.
doi: 10.1002/mrd.23640. Epub 2022 Aug 20.

The role of mtDNA in oocyte quality and embryo development

Justin C St John  1 , Takashi Okada  1 , Eryk Andreas  1 , Alexander Penn  1
Affiliations
Review

The role of mtDNA in oocyte quality and embryo development

Justin C St John et al. Mol Reprod Dev. 2023 Jul.

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.

Keywords: genomic balance; mitochondrial DNA; mitochondrial supplementation; nuclear transfer; oogenesis.

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Conflict of interest statement

The authors declare no conflict of interest.

Figures

Figure 1
Figure 1
The porcine mitochondrial genome. (a) The porcine mitochondrial genome is 16.7 kb in size and encodes 13 of the subunits of the electron transfer chain, namely ND1 to 6 and ND4L, CYTB, COX I to III, and ATP6 and ATP8. It also encodes 2 rRNAs (12S and 16S rRNAs), and 22 tRNAs. It contains two noncoding regions. The smaller region is located two‐thirds of the way around the genome and houses the origin of L‐strand replication (OL). The major noncoding region is the D‐Loop, which contains the regulatory regions, the H‐strand promoter region (HSP), the L‐strand promoter region (LSP), and the origin of H‐strand replication (OH). (b) The D‐Loop (mt. 15,434 to mt. 16,679) also contains two hypervariable regions I and II, the central conserved domain, and three conserved sequence boxes (CSB1‐). rRNA, ribosomal RNA; tRNA, transfer RNA.
Figure 2
Figure 2
The mitochondrial replication machinery mtDNA replication is dependent on nuclear‐encoded mtDNA‐specific transcription and replication factors that translocate to the mitochondrion. Firstly, mtDNA transcription is initiated, which is a pre‐requisite for replication to proceed. The key factors involved in mtDNA replication are POLGA, POLGB, TWNK, TOP1MT, and MTSSB. Each is specific to mtDNA replication only. ETC, electron transfer chain; mtDNA, mitochondrial DNA.
Figure 3
Figure 3
The strict regulation of mtDNA copy number during development During oogenesis, mtDNA copy number exponentially increases to reach a peak at fertilization. Failure of the maturing oocyte to increase mtDNA copy number above the threshold (dotted blue line) can result in fertilization failure or early embryo arrest. mtDNA copy number per cell progressively decreases during preimplantation development until the blastocyst stage when replication is initiated in the trophectoderm only. The inner cell mass cells continue to reduce mtDNA copy number and the “mtDNA set point” is established, which is essential for mature cells to acquire the required numbers of mtDNA copy as their precursor cells undergo differentiation into their mature, fully functional forms. mtDNA, mitochondrial DNA.
Figure 4
Figure 4
Genomic balance. At key stages in development, a cell strikes a balance between its two genomes in order that it can progress to the next stage of development. This process is mediated by the constant exchange of regulatory information between the nucleus and the mitochondrial genome. This ensures that the cell at any given stage acquires sufficient copies of mtDNA in order that the cell can undertake its specialized function using as much or as little ATP derived through OXPHOS. At the same time, the nuclear genome contributes to genomic balance through epigenetic changes by altering, for example, the levels of DNA methylation, that control gene expression. Other factors include DNA rearrangements, such as mutations and deletions, and copy number variants that will have an impact on phenotype. The mitochondrial genome will contribute through the levels of mtDNA copy number available that will influence the means of cellular metabolism available to the cell, which, is also influenced by the cell's mtDNA haplotype. This results in metabolic factors being released that regulate DNA methylation and other epigenetic modifiers, which act on both the nuclear and mitochondrial genomes. mtDNA, mitochondrial DNA; OXPHOS, oxidative phosphorylation.
Figure 5
Figure 5
Utilization of SCNT to promote pig breeding lines. The somatic cell is depleted of its mtDNA and introduced into an oocyte containing mtDNA from a specific mtDNA haplotype (e.g., A, D, or E). Once activated, it can develop into an embryo and give rise to offspring. This allows for embryos and offspring to be studied to determine if mtDNA haplotypes influence phenotypic traits with the aim of generating enhanced lines of breeding pigs. mtDNA, mitochondrial DNA; SCNT, somatic cell nuclear transfer.
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