Abstract
The generally accepted theory of the genetic drift of mitochondrial alleles during mammalian ontogenesis is based on the presence of a selective bottleneck in the female germline. However, there is a variety of different theories on the pathways of genetic regulation of mitochondrial DNA (mtDNA) dynamics in oogenesis and adult somatic cells. The current review summarizes present knowledge on the natural mechanisms of mitochondrial genome elimination during mammalian development. We also discuss the variety of existing and developing methodologies for artificial manipulation of the mtDNA heteroplasmy level. Understanding of the basics of mtDNA dynamics will shed the light on the pathogenesis and potential therapies of human diseases associated with mitochondrial dysfunction.
Highlights
Ten years after the discovery of the DNA double helix, Magrit and Sylvan Nass found that mitochondria harbor their own double-stranded DNA, whose structure differs from the nuclear DNA [1]
It is established that human circular mitochondrial DNA (mtDNA) of 16,659 bp in length encodes 37 genes, which are essential for oxidative phosphorylation (OXPHOS) and stable energy production by the cell [2,3]
It is believed that due to the proximity of the respiratory chain complexes, the absence of histones on mtDNA, and the lack of effective mechanisms of mtDNA repair, the mitochondrial genome is extremely vulnerable to the effects of reactive oxygen species (ROS)
Summary
Ten years after the discovery of the DNA double helix, Magrit and Sylvan Nass found that mitochondria harbor their own double-stranded DNA (mitochondrial DNA, mtDNA), whose structure differs from the nuclear DNA [1]. Considering the increased mutation rate of mtDNA comparing to the nuclear DNA, defective copies of mtDNA could coexist with wild-type alleles in a cell [14,15,16,17]. This phenomenon referred as heteroplasmy is specific to mitochondrial genome. The level of heteroplasmy may vary between the cells of the same tissue or organ, between the organs in one individual, and between individuals in a single family [18] Such heterogeneity may occur at different developmental stages and proceed in an unpredictable direction. We provide specific examples of how these mechanisms can be used for uncovering the pathogenesis and rising novel therapies of mitochondrial dysfunction-associated diseases
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