Transmission of mitochondrial DNA following assisted reproduction and nuclear transfer

Abstract

Mitochondria are the organelles responsible for producing the majority of a cell's ATP and also play an essential role in gamete maturation and embryo development. ATP production within the mitochondria is dependent on proteins encoded by both the nuclear and the mitochondrial genomes, therefore co-ordination between the two genomes is vital for cell survival. To assist with this co-ordination, cells normally contain only one type of mitochondrial DNA (mtDNA) termed homoplasmy. Occasionally, however, two or more types of mtDNA are present termed heteroplasmy. This can result from a combination of mutant and wild-type mtDNA molecules or from a combination of wild-type mtDNA variants. As heteroplasmy can result in mitochondrial disease, various mechanisms exist in the natural fertilization process to ensure the maternal-only transmission of mtDNA and the maintenance of homoplasmy in future generations. However, there is now an increasing use of invasive oocyte reconstruction protocols, which tend to bypass mechanisms for the maintenance of homoplasmy, potentially resulting in the transmission of either form of mtDNA heteroplasmy. Indeed, heteroplasmy caused by combinations of wild-type variants has been reported following cytoplasmic transfer (CT) in the human and following nuclear transfer (NT) in various animal species. Other techniques, such as germinal vesicle transfer and pronuclei transfer, have been proposed as methods of preventing transmission of mitochondrial diseases to future generations. However, resulting embryos and offspring may contain mtDNA heteroplasmy, which itself could result in mitochondrial disease. It is therefore essential that uniparental transmission of mtDNA is ensured before these techniques are used therapeutically.

Expression of mitochondrial transcription factor A (TFAM) during porcine gametogenesis and preimplantation embryo development

“…Perinuclear mitochondrial clustering likely reflects the increased need for energy in the form of mitochondrionproduced ATP to fuel the nuclear events during oocyte maturation and preimplantation embryo development. Accordingly, mitochondrial numbers increase during oocyte maturation in direct proportion to an increased copy number of mtDNA (Sun et al, 2001;El Shourbagy et al, 2006;Spikings et al, 2006), and the high ATP concentration in the oocytes correlates with higher blastocyst rates in bovine embryos and greater in vitro fertilization success in humans (Reynier et al, 2001;Barritt et al, 2002;May-Panloup et al, 2006;Spikings et al, 2007). The mtDNA copy number is dependent on replication factors and transcription factors, such as TFAM (Spikings et al, 2007).…”

Segregation of Naturally Occurring Mitochondrial DNA Variants in a Mini-Pig Model

“…A mother affected by mitochondrial disease can be diagnosed for mtDNA heteroplasmy to determine whether she would be at risk of transmitting the disease to her child (Hellebrekers et al 2012). Moreover, healthy mothers can be carriers and transmit a mtDNA defect (Chinnery et al 1998;Spikings et al 2006). In both cases, the defect would have originated from the population of mtDNA that segregated to the primordial germ cells during early fetal development (Cree et al 2008;Rebolledo-Jaramillo et al 2014).…”

Developmental competence of gametes reconstructed by germinal vesicle transplantation from fresh and cryopreserved bovine oocytes

“…GVT has been indicated as a possible treatment to correct age-related aneuploidy caused by dysfunctional ooplasm (15,20) and as a therapeutic advancement which could help prevent the transmission of mutated mitochondrial DNA from mother to offspring (21)(22)(23).…”