Mitochondria are vital energy-producing organelles within eukaryotic cells, possessing genomes (mitochondrial DNA, mtDNA) that replicate, degrade and develop mutations ( Rand, 2001 Wallace and Chalkia, 2013). Future work will need to test these suggestions, and link mathematical understanding of mitochondria with healthcare data. provide examples using this new theoretical model to suggest therapeutic strategies for diseases caused by mitochondrial DNA mutations. Furthermore, an analytic mathematical description that describes in detail how bottlenecking might work is produced.įinally, Johnston et al. These findings are confirmed using new experimental data from mice, which are genetically distinct from existing studies, illustrating the generality of the model's findings. This reconciles a debate amongst previous studies. find support for two ways that cells segregate mitochondria as they multiply, and show that the decrease in the number of mitochondrial DNA molecules during bottlenecking is flexible. This model starts from the viewpoint that the hundreds or thousands of mitochondrial DNA molecules in a cell can be thought of as a population undergoing random ‘birth’ and ‘death’, and it allows the first statistical comparison of the many proposed bottleneck mechanisms. This approach allowed a new theoretical model of mitochondrial DNA during the growth of an organism to be produced, which encompasses a wide range of existing theories and allows them to be compared. have now used tools from maths, statistics and new experiments to address this debate, in the light of several studies that measured the mitochondrial DNA content in developing mice. The increase in this cell-to-cell variability is called ‘bottlenecking’, and its mechanism remains highly debated. This potentially allows cells with the greatest number of defective mitochondria to be eliminated. If the original egg cell contained defective mitochondrial DNA, some of these new cells end up containing more defective copies than others, leading to cell-to-cell differences in the developing embryo. After fertilisation, the egg divides, the number of cells in the developing embryo increases, and the number of mitochondrial DNA molecules per cell changes. This question is important because inherited mistakes in mitochondrial DNA can have detrimental consequences on health, with links to fatal diseases and many other conditions.Īn unfertilised egg cell contains many copies of mitochondrial DNA molecules some may have mutations and some may not. Mitochondrial DNA is inherited from mothers via the egg, and the details of this inheritance are poorly understood. DNA contained within mitochondria encodes important mitochondrial machinery, and most human cells contain hundreds or thousands of mitochondrial DNA molecules in addition to the DNA that is stored in the nucleus.
Mitochondria are structures that provide vital sources of energy in our cells. We analytically solve a mathematical description of this mechanism, computing probabilities of mtDNA disease onset, efficacy of clinical sampling strategies, and effects of potential dynamic interventions, thus developing a quantitative and experimentally-supported stochastic theory of the bottleneck.
New experimental measurements from a wild-derived mtDNA pairing in mice confirm the theoretical predictions of this model. Using approximate Bayesian computation and mouse data, we find most statistical support for a combination of binomial partitioning of mtDNAs at cell divisions and random mtDNA turnover, meaning that the debated exact magnitude of mtDNA copy number depletion is flexible. We produce a new, physically motivated, generalisable theoretical model for mtDNA populations during development, allowing the first statistical comparison of proposed bottleneck mechanisms.
Uncertainty surrounding this process limits our ability to address inherited mtDNA diseases. Dangerous damage to mitochondrial DNA (mtDNA) can be ameliorated during mammalian development through a highly debated mechanism called the mtDNA bottleneck.
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