| Popis: |
Mitochondria are organelles located inside eukaryotic cells that play several key cellular roles, including providing energy (i.e., ATP), participating in cell signaling, triggering cell differentiation, and initiating apoptosis. All organisms are believed to have low levels of variation in mitochondrial DNA (mtDNA), and repeated mitotic segregation and clonal expansion can enable a mitochondrion to eventually dominate the mtDNA pool. Alterations in mtDNA are connected to a range of human health conditions, including: epilepsy, heart failure, Parkinson's disease, diabetes, and multiple sclerosis. Therefore, understanding how changes in mtDNA accumulate over time and are correlated to changes in mitochondrial function and cell properties can have a profound impact on our understanding of fundamental mammalian cell biology and the origins of some human diseases. Motivated by this, we develop and study a mathematical model to determine which cellular parameters have the largest impact on mtDNA population dynamics. The model consists of coupled differential equations to describe subpopulations of healthy and dysfunctional mitochondria subject to mitochondrial fission, fusion, autophagy, and mutation, and varying levels of cellular ATP, which depend on ATP generation during fusion and energy dissipation by fission and other cellular mechanisms. We study the time evolution of each sub-population under specific selection biases and pressures by tuning specific terms in our model and obtain a phase diagram in the parameter space of the ratio of the rates of fusion, mutation, and autophagy of the healthy and dysfunctional populations. The study complements experiments, where it is often difficult to tune one parameter at a time. Our results may provide insights into how sub-populations of mitochondria survive and evolve under different selection pressures and with time. |
