Review
Replication stress in mitochondria

https://doi.org/10.1016/j.mrfmmm.2018.01.005Get rights and content

Highlights

  • ā€¢

    Mitochondria and mtDNA are heterogeneous under many aspects.

  • ā€¢

    MtDNA replication requires mitochondrial and nuclear factors.

  • ā€¢

    Threats to mtDNA replication arise from the structure/organization of this genome.

  • ā€¢

    Sub-optimal mtDNA replication is associated with disease.

  • ā€¢

    The mtDNA content is not necessarily associated to the mitochondrial mass.

Abstract

Mitochondrial DNA (mtDNA), which is essential for mitochondrial and cell function, is replicated and transcribed in the organelle by proteins that are entirely coded in the nucleus. Replication of mtDNA is challenged not only by threats related to the replication machinery and orchestration of DNA synthesis, but also by factors linked to the peculiarity of this genome. Indeed the architecture, organization, copy number, and location of mtDNA, which are markedly distinct from the nuclear genome, require ad hoc and complex regulation to ensure coordinated replication. As a consequence sub-optimal mtDNA replication, which results from compromised regulation of these factors, is generally associated with mitochondrial dysfunction and disease. Mitochondrial DNA replication should be considered in the context of the organelle and the whole cell, and not just a single genome or a single replication event. Major threats to mtDNA replication are linked to its dependence on both mitochondrial and nuclear factors, which require exquisite coordination of these crucial subcellular compartments. Moreover, regulation of replication events deals with a dynamic population of multiple mtDNA molecules rather than with a fixed number of genome copies, as it is the case for nuclear DNA. Importantly, the mechanistic aspects of mtDNA replication are still debated. We describe here major challenges for human mtDNA replication, the mechanistic aspects of the process that are to a large extent original, and their consequences on disease.

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 ā€œloopā€ of either ssDNA (although likely coated with mtSSB) or a RNA/DNA hybrid, for up to 40ā€“60ā€Æmin 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, ā€œidleā€,

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 (ā‰ˆ80 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 ā€œOn the origin of mitosing cellsā€ that opened the modern view of the endosymbiotic origin of mitochondria and the eukaryote cell.

References (90)

  • D.A. Clayton

    Replication of animal mitochondrial DNA

    Cell

    (1982)
  • W.L. Fangman et al.

    A question of time: replication origins of eukaryotic chromosomes

    Cell

    (1992)
  • T.J. Nicholls et al.

    In D-loop: 40 years of mitochondrial 7S DNA

    Exp. Gerontol.

    (2014)
  • D.F. Bogenhagen et al.

    The mitochondrial DNA replication bubble has not burst

    Trends Biochem. Sci.

    (2003)
  • I.J. Holt et al.

    Coupled leading- and lagging-strand synthesis of mammalian mitochondrial DNA

    Cell

    (2000)
  • D.P. Tapper et al.

    Mechanism of replication of human mitochondrial DNA: localization of the 5' ends of nascent daughter strands

    J. Biol. Chem.

    (1981)
  • G.L. Ciesielski et al.

    Animal mitochondrial DNA replication

    Enzymes

    (2016)
  • A.W. El-Hattab et al.

    Mitochondrial DNA maintenance defects

    Biochim. Biophys. Acta

    (2017)
  • M.J. Young et al.

    Human mitochondrial DNA replication machinery and disease

    Curr. Opin. Genet. Dev.

    (2016)
  • G. Bresciani et al.

    Manganese superoxide dismutase and oxidative stress modulation

    Adv. Clin. Chem.

    (2015)
  • K. Khrapko et al.

    Mitochondrial DNA mutations in aging

    Prog. Mol. Biol. Transl. Sci.

    (2014)
  • J.R. Chapman et al.

    Playing the end game: DNA double-strand break repair pathway choice

    Mol. Cell

    (2012)
  • M. Saki et al.

    DNA damage related crosstalk between the nucleus and mitochondria

    Free Radic. Biol. Med.

    (2017)
  • A. Kaniak-Golik et al.

    Mitochondria-nucleus network for genome stability

    Free Radic. Biol. Med.

    (2015)
  • A.R. Choudhury et al.

    Mitochondrial determinants of cancer health disparities

    Semin. Cancer Biol.

    (2017)
  • Y. Wang et al.

    Triad of risk for late onset Alzheimer's: mitochondrial haplotype, APOE genotype and chromosomal sex

    Front Aging Neurosci.

    (2016)
  • M.S. Sharpley et al.

    Heteroplasmy of mouse mtDNA is genetically unstable and results in altered behavior and cognition

    Cell

    (2012)
  • J.E. Feagin

    The 6-kb element of Plasmodium falciparum encodes mitochondrial cytochrome genes

    Mol. Biochem. Parasitol.

    (1992)
  • J.D. Cupp et al.

    Minireview: DNA replication in plant mitochondria

    Mitochondrion

    (2014)
  • W.F. Martin et al.

    Endosymbiotic theories for eukaryote origin

    Philos. Trans. R. Soc. Lond. B Biol. Sci.

    (2015)
  • C.A. Steward et al.

    Genome annotation for clinical genomic diagnostics: strengths and weaknesses

    Genome Med.

    (2017)
  • L. Sagan

    On the origin of mitosing cells

    J. Theor. Biol.

    (1967)
  • A.A. Kolesnikov et al.

    Diversity of mitochondrial genome organization

    Biochemistry (Mosc).

    (2012)
  • D.V. Lavrov et al.

    Animal mitochondrial DNA as we do not know it: mt-genome organization and evolution in nonbilaterian lineages

    Genome Biol. Evol.

    (2016)
  • D.B. Sloan et al.

    Rapid evolution of enormous, multichromosomal genomes in flowering plant mitochondria with exceptionally high mutation rates

    PLoS Biol.

    (2012)
  • L. Chatre et al.

    Prevalent coordination of mitochondrial DNA transcription and initiation of replication with the cell cycle

    Nucleic Acids Res.

    (2013)
  • K. Mitra et al.

    A hyperfused mitochondrial state achieved at G1-S regulates cyclin E buildup and entry into S phase

    Proc. Natl. Acad. Sci. U. S. A.

    (2009)
  • L. Chatre et al.

    Large heterogeneity of mitochondrial DNA transcription and initiation of replication exposed by single-cell imaging

    J. Cell Sci.

    (2013)
  • D.C. Wallace et al.

    Mitochondrial DNA genetics and the heteroplasmy conundrum in evolution and disease

    Cold Spring Harb. Perspect. Biol.

    (2013)
  • X. Sun et al.

    The role of the mtDNA set point in differentiation, development and tumorigenesis

    Biochem. J.

    (2016)
  • D.C. Wallace

    Mitochondria and cancer

    Nat. Rev. Cancer

    (2012)
  • Y. He et al.

    Heteroplasmic mitochondrial DNA mutations in normal and tumour cells

    Nature

    (2010)
  • A.V. Kuznetsov et al.

    Heterogeneity of mitochondria and mitochondrial function within cells as another level of mitochondrial complexity

    Int. J. Mol. Sci.

    (2009)
  • D.C. Woods

    Mitochondrial heterogeneity: evaluating mitochondrial subpopulation dynamics in stem cells

    Stem Cells International

    (2017)
  • G. Benard et al.

    Physiological diversity of mitochondrial oxidative phosphorylation

    Am. J. Physiol. Cell Physiol.

    (2006)
  • Cited by (8)

    • Boosting mitochondrial health to counteract neurodegeneration

      2022, Progress in Neurobiology
      Citation Excerpt :

      Top-down approaches, on the other hand, promote overall mitochondrial resilience and health by enhancing the capacity of mitochondria to deal with stressors. Mitochondria in fact are increasingly acknowledged as crucial components in rapid adaptations to changing environmental or metabolic stressors in aerobic organisms (Ricchetti, 2018; Schuler et al., 2021). How specific top-down strategies work mechanistically warrants further investigation.

    • Air pollution and placental mitochondrial DNA copy number: Mechanistic insights and epidemiological challenges

      2019, Environmental Pollution
      Citation Excerpt :

      Suppose that the lower mtDNA exhibited a change of phenotype and function in the placenta, then it would affect birth outcomes. Placental mtDNA copy number may be partly determined by the replication models (Yasukawa and Kang, 2018), the abundance raw materials of DNA including primers and nucleotides, and by the complex interactions of these factors with other organelles, such as the nucleus (Ricchetti, 2018). These events therefore need to be analyzed in the context of the organelle and the whole cell and not just a single replication event (Ricchetti, 2018).

    • Broad spectrum metabolomics for detection of abnormal metabolic pathways in a mouse model for retinitis pigmentosa

      2019, Experimental Eye Research
      Citation Excerpt :

      Mitochondrial DNA replication and repair are processes that occurs during mitochondrial dynamics. Therefore, deoxyribonucleotides and related metabolites involved in pyrimidine and purine pathways are critical for mitochondrial survival and function (Ricchetti, 2018). In both pyrimidine and purine pathways, we observed significantly altered ratios of metabolites in comparisons between rd10 and wild type mice when reared in either light or dark conditions (Figs. 5 and 6).

    • Special section: Replication stress, a threat to the nuclear and mitochondrial genome

      2018, Mutation Research - Fundamental and Molecular Mechanisms of Mutagenesis
    View all citing articles on Scopus
    View full text