Abstract
Translocation of mtDNA in the nuclear genome is an ongoing process that contributes to the development of pathological conditions in humans. However, the causal factors of this biological phenomenon in human cells are poorly studied. Here we analyzed mtDNA insertions in the nuclear genome of human lymphocytes after in vitro treatment with doxorubicin (DOX) using a fluorescence in situ hybridization (FISH) technique. The number of mtDNA insertions positively correlated with the number of DOX-induced micronuclei, suggesting that DOX-induced chromosome breaks contribute to insertion events. Analysis of the odds ratios (OR) revealed that DOX at concentrations of 0.025 and 0.035 µg/mL significantly increases the rate of mtDNA insertions (OR: 3.53 (95% CI: 1.42–8.76, p < 0.05) and 3.02 (95% CI: 1.19–7.62, p < 0.05), respectively). Analysis of the distribution of mtDNA insertions in the genome revealed that DOX-induced mtDNA insertions are more frequent in larger chromosomes, which are more prone to the damaging action of DOX. Overall, our data suggest that DOX-induced chromosome damage can be a causal factor for insertions of mtDNA in the nuclear genome of human lymphocytes. It can be assumed that the impact of a large number of external and internal mutagenic factors contributes significantly to the origin and amount of mtDNA in nuclear genomes.
Highlights
The endosymbiotic hypothesis suggests that mitochondria were free-living cells that colonize at least one single cell
De novo mtDNA transfer of mitochondrial DNA into the nuclear genome has been reported in cells of patients with various pathologies [5,6,7,8,10], the possibility of mutagen-induced nuclear transfer of mtDNA has not been comprehensively studied to our knowledge, with the only exception being transfer in chick embryos from eggs exposed to X-rays [23]
We have shown that DOX at concentrations inducing chromosomal instability and detected by micronucleus test, is capable of promoting mtDNA translocation into nuclear genome of human lymphocytes, which is significantly correlated with DOX-induced micronuclei level
Summary
The endosymbiotic hypothesis suggests that mitochondria were free-living cells that colonize at least one single cell. Millions of years of co-evolution resulted in the transfer of a large number of genes from mitochondria to the nucleus [1]. There are two types of mitochondrial DNA (mtDNA) in the nucleus. First are nuclear DNA sequences encoding proteins (~2000) for the proper function of mitochondria, as they are no longer present in the DNA of mitochondria. The second are nuclear DNA sequences that are copies of existing mtDNA. These sequences, known as nuclear DNA sequences of mitochondrial origin or NUMTs (pronounced “new-mights”), can be detected in at least 85 sequenced eukaryotic genomes [2]. Over 750 NUMTs have been identified in human reference genome and new insertions may occur at a rate of ~5 × 10−6 per germ cell per generation [1,3]
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
