Abstract
Studies of mitochondrial (mt)DNA replication, which forms the basis of mitochondrial inheritance, have demonstrated that a rolling-circle replication mode exists in yeasts and human cells. In yeast, rolling-circle mtDNA replication mediated by homologous recombination is the predominant pathway for replication of wild-type mtDNA. In human cells, reactive oxygen species (ROS) induce rolling-circle replication to produce concatemers, linear tandem multimers linked by head-to-tail unit-sized mtDNA that promote restoration of homoplasmy from heteroplasmy. The event occurs ahead of mtDNA replication mechanisms observed in mammalian cells, especially under higher ROS load, as newly synthesized mtDNA is concatemeric in hydrogen peroxide-treated human cells. Rolling-circle replication holds promise for treatment of mtDNA heteroplasmy-attributed diseases, which are regarded as incurable. This review highlights the potential therapeutic value of rolling-circle mtDNA replication.
Highlights
The mitochondria, which provide eukaryotic cells with energy through oxidative phosphorylation, contain multiple copies of mitochondrial DNA. mtDNA encodes components essential for ATP production [1,2]
When pulsed-field gel electrophoresis (PFGE) is used to separate human mtDNA species from nuclear genomic DNA species followed by Southern blot analysis with an mtDNA-specific probe, the majority of mtDNA molecules observed as mtDNA signals remain stuck inside the wells [18]
We introduced the rolling-circle type mtDNA replication mode driven by mitochondrial homologous recombination and described its potential importance for maintaining a healthy lifespan, preventing mitochondrial diseases, and understanding the nature of the mtDNA genetic bottleneck during oogenesis
Summary
The mitochondria, which provide eukaryotic cells with energy through oxidative phosphorylation, contain multiple copies of mitochondrial DNA (mtDNA). mtDNA encodes components essential for ATP production [1,2]. It is widely believed that mitochondria are descended from endosymbiotic bacteria [26] In bacteria such as Escherichia coli, homologous recombination–dependent DNA replication proceeds by the θ-type mode or rolling-circle mode of DNA synthesis, yielding closed-circular DNA monomers or linear-stranded DNA multimers, respectively [27]. It remains unknown which DNA replication mode is preferred in mitochondria, and forms the basis of mtDNA inheritance [14,28,29]. Homologous DNA pairing mediates both ROS-stimulated rolling-circle mtDNA replication, which promotes mitochondrial allele segregation toward homoplasmy, and homologous DNA recombination, which is crucial for the repair of harmful mtDNA double-stranded breaks (DSBs), and for maintenance of cellular respiration
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