mtDNA is primarily inherited from the population that is present in the primordial germ cells, which are the very first germ cells laid post-gastrulation (36) (Figure 7). This population of about 200 copies of mtDNA serves as a template that is replicated during the process of oogenesis as these undifferentiated cells differentiate into mature, fertilisable, metaphase II oocytes which possess between 150,000 and 250,000 copies of mtDNA, an increase in copy number of ~1000-fold (37-39) (Figure 7). The amount of mtDNA present in the mature oocyte is considered to be an investment in subsequent development post-fertilisation (40). This arises as the mtDNA content decreases significantly during preimplantation development (41). Indeed, the shedding of mtDNA is considered to be an active process that is indicative of early embryonic regulation that enhances implantation outcome (42). Once the preimplantation embryo reaches the blastocyst stage, which is the first stage of compartmentalisation of the new embryo, the trophectoderm and the inner cell mass cells are formed. The trophectodermal cells have initiated lineage commitment whilst the inner cell mass cells maintain a naïve state that has been indicative of all embryonic cells to this stage of development. In line with lineage specialisation, mtDNA replication is initiated in the trophectodermal cells (Figure 7), which give rise to the placenta, and likely supports the energy requirements that promote the process of implantation (41).
The inner cell mass cells, which give rise to the embryo proper and to the fetus, continue to dilute out their mtDNA content (41) until they establish the mtDNA set point (40, 43, 44) (Figure 7). The mtDNA set point is defined as the minimum amount of mtDNA template required to support mtDNA replication that is initiated post-gastrulation, as these naïve cells progress to specialised states and will give rise to all cell types of the body (21). This provides the cells that give rise to, for example, neurons, muscles and heart cells with the potential to replicate their mtDNA copy number to high levels so that they utilise OXPHOS to support their complex cellular functions (45) (Figure 7). Other cell types, such as blood cells and sperm cells, maintain low levels of mtDNA content (Figure 7) and, consequently, do not rely on OXPHOS but rather glycolysis for their generation of ATP (45).
In the vast majority of cases, mtDNA is inherited from the expanded population of mtDNA copies that are present in the egg at the time of fertilisation. However, this population is refined once the set point is established, and the mtDNA genetic bottleneck, a cleansing process that takes place pre-gastrulation, results in approximately 200 copies of mtDNA being the ‘true’ units of inheritance (37-39). This selection pressure and mechanism for transmission of a purified population of mtDNA is, therefore, a maternal only transmission process (46). However, it has been demonstrated in some lower order species such as drosophila (47) and mussels (48, 49) that paternal mtDNA can be identified in embryos and offspring. Indeed, some species of mussels have M (male) and F (female) mitochondrial genomes with males inheriting both M and F genotypes whilst females inherit F genotypes only (49). In mice, paternal mtDNA is transmitted at very low levels, usually 1% or less, but this is restricted to interspecific crossings, i.e. when both parents originate from different breeds or strains (50).
In humans, it is evident that mtDNA is maternally only inherited. However, there has been one reported clinical case where an individual inherited mtDNA from his father’s sperm (51). In this case, it was detected as a de novo mutation that led to a severe mitochondrial myopathy. Furthermore, sperm mtDNA is present in abnormal human triploid embryos (52). Indeed, the failure to eliminate sperm mtDNA can lead to embryonic lethality (53).
