Pavlov Sergei, Duk Maria, Gursky Vitaly V, Samsonova Maria, Kanapin Alexander, Samsonova Anastasia
Mathematical Biology and Bioinformatics Laboratory, Peter the Great Saint Petersburg Polytechnic University, Saint Petersburg 195251, Russia.
Theoretical Department, Ioffe Institute, Saint Petersburg 194021, Russia.
Life (Basel). 2025 Aug 23;15(9):1338. doi: 10.3390/life15091338.
Retrotransposons exhibit increased activity in cancer cells. One possible approach to anticancer therapy is to use this activity to influence the energy balance in cells. Abnormal distribution of retrotransposons in the genome requires additional energy consumption, which can lead to a significant decrease in the total amount of free ATP molecules in the cell. A decrease in ATP levels below a certain threshold can in turn trigger a cell death program. To investigate the possibility of such a scenario, we developed a mathematical model of the cellular energy balance that describes the dynamics of energy consumption by the main cellular processes, including costs of retrotransposon activity. The model considers changes in the concentrations of ATP, active retrotransposons (LINE-1 and SINE) in the human genome, as well as mRNAs and proteins that are expression products of retrotransposon and constitutive genes. We estimated the parameter values in the model based on literature data and numerical optimization. We found a single stable stationary solution, characterized by low retrotransposon activity, and used it as the reference steady state for further analysis. Parametric sensitivity analysis revealed the parameters whose changes had the greatest impact on cellular ATP levels. The LINE-1 deactivation rate constant and the maximum LINE-1 transcription rate were the most sensitive among the transposon-related parameters. Perturbation of these parameters led to a decrease in the number of free ATP to 30% of the reference value and below. Transcription of retrotransposons under perturbed parameters became comparable to the translation of constitutive genes in terms of energy costs. The presented results indicate that cancer cell death can be initiated by increasing the load on the energy balance due to the activation of transposons.
逆转录转座子在癌细胞中表现出更高的活性。一种可能的抗癌治疗方法是利用这种活性来影响细胞内的能量平衡。逆转录转座子在基因组中的异常分布需要额外的能量消耗，这可能导致细胞中游离ATP分子总量显著减少。ATP水平降至一定阈值以下反过来会触发细胞死亡程序。为了研究这种情况的可能性，我们开发了一个细胞能量平衡的数学模型，该模型描述了包括逆转录转座子活性成本在内的主要细胞过程的能量消耗动态。该模型考虑了人类基因组中ATP、活性逆转录转座子（LINE-1和SINE）的浓度变化，以及作为逆转录转座子和组成型基因表达产物的mRNA和蛋白质。我们根据文献数据和数值优化估计了模型中的参数值。我们发现了一个单一的稳定稳态解，其特征是逆转录转座子活性较低，并将其用作进一步分析的参考稳态。参数敏感性分析揭示了那些变化对细胞ATP水平影响最大的参数。在与转座子相关的参数中，LINE-1失活速率常数和LINE-1最大转录速率最为敏感。这些参数的扰动导致游离ATP数量减少至参考值的30%及以下。在参数扰动下，逆转录转座子的转录在能量成本方面变得与组成型基因的翻译相当。所呈现的结果表明，由于转座子的激活增加了能量平衡的负担，从而可以引发癌细胞死亡。
