NAR Mol Med. 2026 Jan;3(1):
ugaf042
For quite some time, knowledge about mitochondria and the mitochondrial genome has been primarily limited to energy production. However, there is now increasing evidence that they have many important roles in cell function and that synergy between the nuclear and mitochondrial genomes is an essential prerequisite to developmental outcome. This review describes the mitochondrial genome and its contribution to overall cellular genomic content; and discusses mitochondrial DNA (mtDNA) inheritance. mtDNA homoplasmy and heteroplasmy are defined and distinctions between pathogenic and non-pathogenic rearrangements are drawn; how they are transmitted; and their effects on oocyte quality and developmental outcomes. This is followed by analysis of mtDNA replication and changes in mtDNA copy number during development; why they need to happen; and how they influence developmental outcomes. Changes to nuclear DNA methylation events are then discussed in the context of changes to mtDNA replication throughout development. This leads to the concept of 'genomic balance', which defines how cells at any stage of development require adjustments to both genomes to ensure successful cellular function and development; and how this process can be perturbed by some of the more invasive assisted reproductive technologies designed to treat infertility and mtDNA disease.