The engulfment of an α-proteobacterium by a precursor of the eukaryotic cell billions of years ago resulted in the modern-day mitochondrion. Mitochondria retain a small amount of their own genetic material, mtDNA. Eleven of these genes encode proteins that form essential subunits of the respiratory chain, whereas the remaining genes encode components necessary for translation.
This circular, double-stranded DNA contains two strands: the so-called heavy strand is enriched with guanine, whereas cytosine dominates the light strand. Guanine has a propensity for oxidation and formation of the common lesion, 8-oxo-7,8-dihydroguanine (8-oxoG). MtDNA is not protected from oxidation by histones like nuclear DNA.. Each cell has many mitochondria and thus multiple mtDNA copies. Importantly, the DNA is physically tethered to the inner mitochondrial membrane in close proximity to the electron transport chain, thereby exposing the mtDNA to damage by electron leak from the respiratory complexes. This leak is the major source of reactive oxygen species (ROS) in human cells and causes far greater damage and oxidative lesions to mtDNA than to nuclear DNA. These lesions increase with age and can promote pathogenic mutations.
Mutations to genes encoding mitochondrial proteins involved in energy production decrease bioenergetic capacity, while specific mtDNA point mutations or deletions cause disease.