Figure 2.

The regulation of mtDNA copy number during development. In primordial germ cells, mtDNA is maintained at low levels. As oogenesis progresses, mtDNA copy number increases significantly and is then arrested at the metaphase II stage. A threshold (broken blue line) needs to be reached in order that oocytes mature and fertilize. Following fertilization, mtDNA copy number decreases through to the blastocyst stage. mtDNA replication is initiated in the trophectoderm, whilst the ICM continues to reduce mtDNA copy number. This enables the developing embryo to establish the mtDNA set point prior to differentiation. Following commitment to a specific lineage, cells then replicate their mtDNA in a cell-specific manner to enable them to perform their specialized functions through OXPHOS, as required. Furthermore, there are synchronous changes to DNA methylation and gene expression profiles throughout these processes. TET enzymes reduce parental DNA methylation through to the blastocyst stage whilst de novo DNA methylation, mediated by DNMT3a and DNMT3b, is initiated in the blastocyst. DNMT1 then maintains the newly established cell-specific DNA methylation profiles.