Mutation Research/Fundamental and Molecular Mechanisms of Mutagenesis
ReviewReplication stress in mitochondria
Section snippets
Structural differences between mitochondrial and nuclear DNA impact on replication strategies
Eukaryote cells are generated from information coded in the nuclear genome and in mitochondrial genomes. Mitochondria, the organelles responsible for production of most cellular ATP via oxidative phosphorylation (OXPHOS), are also implicated in calcium homeostasis, regulation of metabolic and signalling pathways, and apoptosis. The mitochondrial genome codes for a few mitochondria proteins, all implicated in OXPHOS, out of about 1500 proteins (in humans) that are necessary for the organelle
Heterogeneity and networking of mitochondria and mtDNA
Mitochondrial DNA can be heterogeneous. The presence of two or more variants of mtDNA at detectable levels is called heteroplasmy, and the mutant variant is generally defective [15], (Fig. 2). As a consequence, heteroplasmy is largely associated with disease (mitochondrial diseases, cancer). MtDNA mutations have been recurrently detected in cancer cells, which require adaptation of mitochondrial energy requirements [16,17]. Cancer cells indeed prevalently switch to aerobic glycolysis rather
Replication of mitochondrial DNA
The mtDNA is organized in nucleoids located in the matrix side of the mitochondrial inner membrane [37]. Nucleoids contains one or a few copies of the mtDNA (on average 1.4 copies/nucleoid, according to most recent estimations [38]) and proteins necessary for replication of mtDNA, mainly the DNA polymerase PolĪ³ (or POLG1) that carries the catalytic subunit, the accessory replication protein POLG2, the Twinkle helicase, the single-strand binding protein mtSSB, and the transcription and DNA
Replication stress
Mechanistic threats affect mtDNA replication with either replication mechanisms. The major risk probably resides in the asynchronous synthesis of DNA that generates a āloopā of either ssDNA (although likely coated with mtSSB) or a RNA/DNA hybrid, for up to 40ā60āÆmin before it is can serve as template for DNA synthesis. During this time, DNA synthesis keeps taking place on the other parental strand. The RNA/DNA hybrid of the booltlace mechanism guarantees high stability of the parental, āidleā,
Nuclear-mitochondrial coordination
Replication and transcription of mtDNA are performed exclusively by nuclear coded-proteins that are subsequently imported in the organelle, thereby requiring efficient nuclear-mitochondrial signalling and mitochondrial transport. Translation of mitochondrial proteins requires further coordination, since the RNA moiety of the protein synthesis apparatus (2 RNA and 22 tRNAs) are all mitochondrial coded, whereas the protein components of mitochondrial ribosome (ā80 proteins) are all nuclear coded
Conclusions
Mitochondrial DNA replication and maintenance are essential processes for mitochondrial and cellular function, and are exquisitely coordinated through both mitochondrial and nuclear events. MtDNA replication, which in vertebrates has several unique features, requires not only coordination and efficiency of the replication process per se, but also control of factors that regulates the distribution, number, and integrity of these multiple genomes, and their dependence of nuclear factors (Fig. 7).
Acknowledgements
This paper is dedicated to the 50th anniversary of the publication of Lynn (Sagan) Margulysā paper āOn the origin of mitosing cellsā that opened the modern view of the endosymbiotic origin of mitochondria and the eukaryote cell.
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