![]() Such mutations have been implicated in a wide range of human pathologies such as sarcopenia, and even ageing. Mitochondrial DNA mutations can lead to the loss of mitochondrial function when the level of mutations exceeds a critical threshold. Mutations in mtDNA can occur during replication and thus mtDNA molecules in a single cell may not share the same sequence, a condition called heteroplasmy. The turnover of mtDNA occurs through replication and degradation of these molecules, which happen along with the biogenesis and autophagy of mitochondria organelles. In contrast to nuclear DNA (nDNA), a single eukaryotic cell can harbor 1,000 s of mtDNA and mtDNA are continuously turned over, independent of the cell cycle. Mitochondria also possess their own genome, mitochondrial DNA (mtDNA), which encodes several key proteins involved in ATP production. ![]() Mitochondria are the powerhouses of eukaryotic cells, whose main function is to produce ATP. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.Ĭompeting interests: The authors have declared that no competing interests exist. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.įunding: This study was supported by funding from ETH Zurich, the National University of Singapore (FRC Grant R-279-000-299-112) and the Ministry of Education Singapore (MOE2010-T2-2-048). Received: JanuAccepted: AugPublished: October 11, 2013Ĭopyright: © 2013 Tam et al. PLoS ONE 8(10):Įditor: Dov Joseph Stekel, University of Nottingham, United Kingdom Our results thus shed light on the interplay between mitochondrial fusion-fission and mtDNA turnover and may explain the mechanism underlying the experimentally observed increase in the accumulation of mtDNA mutations when either mitochondrial fusion or fission is inhibited.Ĭitation: Tam ZY, Gruber J, Halliwell B, Gunawan R (2013) Mathematical Modeling of the Role of Mitochondrial Fusion and Fission in Mitochondrial DNA Maintenance. However, our simulations suggest that the protective ability of retrograde signalling depends on the efficiency of fusion-fission process. When these mutations affect cellular energetics, nuclear retrograde signalling can upregulate mtDNA replication, which is expected to slow clonal expansion of these mutant mtDNA. Consequently, slower mitochondrial fusion-fission results in higher variability in the mtDNA mutation burden among cells in a tissue over time, and mtDNA mutations have a higher propensity to clonally expand due to the increased stochasticity. Here we report model simulations suggesting that when mitochondrial fusion-fission rate is low, the slow mtDNA mixing can lead to an uneven distribution of mutant mtDNA among mitochondria in between two mitochondrial autophagic events leading to more stochasticity in the outcomes from a single random autophagic event. In this study, an in silico modeling approach is taken to investigate the effects of mitochondrial fusion and fission dynamics on mutant mtDNA accumulation. While the expansion of a mutant mtDNA population is believed to occur by random segregation of these molecules during turnover, the role of mitochondrial fusion-fission in this context is currently not well understood. replicated and degraded) and are also exchanged among mitochondria during the fusion and fission of these organelles. In cells, mtDNA molecules are constantly turned over (i.e. Accumulation of mitochondrial DNA (mtDNA) mutations has been implicated in a wide range of human pathologies, including neurodegenerative diseases, sarcopenia, and the aging process itself.
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