The engulfment of an α-proteobacterium by a precursor of the eukaryotic cell billions of years ago, accompanied by the loss of most of the genetic material to the nucleus, resulted in the modern-day mitochondrion. Mitochondria retain a small amount of their own genetic material, mtDNA, to generate key proteins. Although the mitochondria contain more than 1000 proteins, most are derived from nuclear DNA. Only a small fraction of these proteins, 37, are encoded by mtDNA; eleven form essential subunits of the respiratory chain, whereas the remaining genes encode components necessary for translation.
Distinguishing this circular, double-stranded 16,568 bp DNA is the nucleotide content of the 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, rather it is packaged within macromolecular units called nucleoids. Each mitochondrion contains about 3.2 nucleoids with 1-2 molecules of mtDNA, while each cell has many mitochondria and thus multiple mtDNA copies. Importantly, the nucleoid 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. The amounts of these lesions increase with age. Moreover, these lesions can promote pathogenic mutations.
Mutated genes (mt or nuclear) encoding mitochondrial proteins involved in energy production decrease bioenergetic capacity, while specific mtDNA point mutations or deletions cause disease. Single nucleotide polymorphisms (point variations in the building DNA building blocks) are also linked with disease risk and even non-pathogenic mtDNA variants can influence pathophysiology.