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Context-Dependent Role of Mitochondrial Fusion-Fission in Clonal Expansion of mtDNA Mutations.

Tam ZY, Gruber J, Halliwell B, Gunawan R - PLoS Comput. Biol. (2015)

Bottom Line: The accumulation of mutant mitochondrial DNA (mtDNA) molecules in aged cells has been associated with mitochondrial dysfunction, age-related diseases and the ageing process itself.Otherwise, faster fusion-fission quickens the accumulation of mutant mtDNA.Finally, we used the insights gained from model simulations and analysis to propose a possible circumstance involving deterioration of mitochondrial QC that permits mutant mtDNA to expand with age.

View Article: PubMed Central - PubMed

Affiliation: Lee Kong Chian School of Medicine, Nanyang Technological University, Singapore.

ABSTRACT
The accumulation of mutant mitochondrial DNA (mtDNA) molecules in aged cells has been associated with mitochondrial dysfunction, age-related diseases and the ageing process itself. This accumulation has been shown to often occur clonally, where mutant mtDNA grow in number and overpopulate the wild-type mtDNA. However, the cell possesses quality control (QC) mechanisms that maintain mitochondrial function, in which dysfunctional mitochondria are isolated and removed by selective fusion and mitochondrial autophagy (mitophagy), respectively. The aim of this study is to elucidate the circumstances related to mitochondrial QC that allow the expansion of mutant mtDNA molecules. For the purpose of the study, we have developed a mathematical model of mitochondrial QC process by extending our previous validated model of mitochondrial turnover and fusion-fission. A global sensitivity analysis of the model suggested that the selectivity of mitophagy and fusion is the most critical QC parameter for clearing de novo mutant mtDNA molecules. We further simulated several scenarios involving perturbations of key QC parameters to gain a better understanding of their dynamic and synergistic interactions. Our model simulations showed that a higher frequency of mitochondrial fusion-fission can provide a faster clearance of mutant mtDNA, but only when mutant-rich mitochondria that are transiently created are efficiently prevented from re-fusing with other mitochondria and selectively removed. Otherwise, faster fusion-fission quickens the accumulation of mutant mtDNA. Finally, we used the insights gained from model simulations and analysis to propose a possible circumstance involving deterioration of mitochondrial QC that permits mutant mtDNA to expand with age.

No MeSH data available.


Appearance and disappearance of mutant-rich mitochondria.The simulations were performed with only mitochondrial fusion-fission process and with non-selective fusion, for (A) τ = 7.5 days and (B) τ = 30 days.
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pcbi.1004183.g005: Appearance and disappearance of mutant-rich mitochondria.The simulations were performed with only mitochondrial fusion-fission process and with non-selective fusion, for (A) τ = 7.5 days and (B) τ = 30 days.

Mentions: We observed the opposite effect of fusion-fission frequency on mutant mtDNA clearance when mitophagy selectivity was significantly increased in the absence of fusion selectivity (see Fig 4A and 4B). In this case, more frequent fusion-fission quickened the removal of mutant mtDNA regardless of RA. The reversal of trend can be explained by considering the time scales of mitochondria harboring a high fraction of mutant mtDNA, which we refer to as mutant-rich mitochondria. Mutant-rich mitochondria can arise randomly during fissions, and disappear by fusing with other mitochondria. To illustrate this phenomenon, we simulated the model with only the fusion-fission process in a cell containing a single mutant mtDNA nucleoid (in the absence of mitochondrial turnover and selectivity of fusion). Fig 5 shows the fractional mutation burden RMmito of the mitochondrion harboring the mutant nucleoid, illustrating the appearance and disappearance of mutant-rich mitochondria. When fusion-fission became more frequent (i.e. for lower τ), mutant-rich mitochondria occurred more frequently (4.1×10–4 day-1mitochondrion-1 for τ = 7.5 days vs. 9.5x10-5 day-1mitochondrion-1 for τ = 30 days). However, with more frequent fusion-fission, these mutant-rich mitochondria had a shorter average lifetime (0.9 days for τ = 7.5 days vs. 3.7 days for τ = 30 days). Nevertheless, the fraction of time that the mtDNA mutant molecule existed in a mutant-rich mitochondrion did not change, since the numbers of fusion and fission events remained at the same ratio. Therefore, while a quicker fusion-fission process could produce more mutant-rich mitochondria, the shorter existence of these mitochondria meant that there was less time for selective mitophagy to remove them. If the time scale of mitophagy was much longer than the duration of these mutant-rich mitochondria, then mutant mtDNA molecules would get diluted among the population of mitochondria, preventing the clearance of such molecules.


Context-Dependent Role of Mitochondrial Fusion-Fission in Clonal Expansion of mtDNA Mutations.

Tam ZY, Gruber J, Halliwell B, Gunawan R - PLoS Comput. Biol. (2015)

Appearance and disappearance of mutant-rich mitochondria.The simulations were performed with only mitochondrial fusion-fission process and with non-selective fusion, for (A) τ = 7.5 days and (B) τ = 30 days.
© Copyright Policy
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4440705&req=5

pcbi.1004183.g005: Appearance and disappearance of mutant-rich mitochondria.The simulations were performed with only mitochondrial fusion-fission process and with non-selective fusion, for (A) τ = 7.5 days and (B) τ = 30 days.
Mentions: We observed the opposite effect of fusion-fission frequency on mutant mtDNA clearance when mitophagy selectivity was significantly increased in the absence of fusion selectivity (see Fig 4A and 4B). In this case, more frequent fusion-fission quickened the removal of mutant mtDNA regardless of RA. The reversal of trend can be explained by considering the time scales of mitochondria harboring a high fraction of mutant mtDNA, which we refer to as mutant-rich mitochondria. Mutant-rich mitochondria can arise randomly during fissions, and disappear by fusing with other mitochondria. To illustrate this phenomenon, we simulated the model with only the fusion-fission process in a cell containing a single mutant mtDNA nucleoid (in the absence of mitochondrial turnover and selectivity of fusion). Fig 5 shows the fractional mutation burden RMmito of the mitochondrion harboring the mutant nucleoid, illustrating the appearance and disappearance of mutant-rich mitochondria. When fusion-fission became more frequent (i.e. for lower τ), mutant-rich mitochondria occurred more frequently (4.1×10–4 day-1mitochondrion-1 for τ = 7.5 days vs. 9.5x10-5 day-1mitochondrion-1 for τ = 30 days). However, with more frequent fusion-fission, these mutant-rich mitochondria had a shorter average lifetime (0.9 days for τ = 7.5 days vs. 3.7 days for τ = 30 days). Nevertheless, the fraction of time that the mtDNA mutant molecule existed in a mutant-rich mitochondrion did not change, since the numbers of fusion and fission events remained at the same ratio. Therefore, while a quicker fusion-fission process could produce more mutant-rich mitochondria, the shorter existence of these mitochondria meant that there was less time for selective mitophagy to remove them. If the time scale of mitophagy was much longer than the duration of these mutant-rich mitochondria, then mutant mtDNA molecules would get diluted among the population of mitochondria, preventing the clearance of such molecules.

Bottom Line: The accumulation of mutant mitochondrial DNA (mtDNA) molecules in aged cells has been associated with mitochondrial dysfunction, age-related diseases and the ageing process itself.Otherwise, faster fusion-fission quickens the accumulation of mutant mtDNA.Finally, we used the insights gained from model simulations and analysis to propose a possible circumstance involving deterioration of mitochondrial QC that permits mutant mtDNA to expand with age.

View Article: PubMed Central - PubMed

Affiliation: Lee Kong Chian School of Medicine, Nanyang Technological University, Singapore.

ABSTRACT
The accumulation of mutant mitochondrial DNA (mtDNA) molecules in aged cells has been associated with mitochondrial dysfunction, age-related diseases and the ageing process itself. This accumulation has been shown to often occur clonally, where mutant mtDNA grow in number and overpopulate the wild-type mtDNA. However, the cell possesses quality control (QC) mechanisms that maintain mitochondrial function, in which dysfunctional mitochondria are isolated and removed by selective fusion and mitochondrial autophagy (mitophagy), respectively. The aim of this study is to elucidate the circumstances related to mitochondrial QC that allow the expansion of mutant mtDNA molecules. For the purpose of the study, we have developed a mathematical model of mitochondrial QC process by extending our previous validated model of mitochondrial turnover and fusion-fission. A global sensitivity analysis of the model suggested that the selectivity of mitophagy and fusion is the most critical QC parameter for clearing de novo mutant mtDNA molecules. We further simulated several scenarios involving perturbations of key QC parameters to gain a better understanding of their dynamic and synergistic interactions. Our model simulations showed that a higher frequency of mitochondrial fusion-fission can provide a faster clearance of mutant mtDNA, but only when mutant-rich mitochondria that are transiently created are efficiently prevented from re-fusing with other mitochondria and selectively removed. Otherwise, faster fusion-fission quickens the accumulation of mutant mtDNA. Finally, we used the insights gained from model simulations and analysis to propose a possible circumstance involving deterioration of mitochondrial QC that permits mutant mtDNA to expand with age.

No MeSH data available.