Biophysical multiscale modeling of mitochondrial swelling

线粒体是细胞的“发电厂”，为无数的过程提供ATP。线粒体内膜（IMM）对ATP的产生至关重要，在维持该细胞器的体积方面起着关键作用。体积的小的可逆变化与线粒体功能的调节有关，而大的不可逆变化导致线粒体功能障碍甚至细胞死亡。线粒体过度膨胀的主要机制包括被称为渗透性过渡孔的通道的打开。从可逆到不可逆肿胀转变的机制尚不清楚。肿胀涉及哪些线粒体内和线粒体外因素？IMM的物理和化学特性是如何协调这一过程的？本项目提出的多尺度生物物理模型将表征线粒体肿胀的所有阶段，从而描述从可逆肿胀到不可逆肿胀的转变机制。该项目将通过应用广泛的实验和建模方法，为这一基本生物过程建立一个更全面的模型。更广泛的影响活动将包括对学生进行数量分析和建模方法方面的培训。该项目的主要目标是基于离子和中性物质通过IMM的动力学和膜的力学特性，建立一个线粒体肿胀的综合模型。该项目旨在通过开发生物物理多尺度模型来模拟和预测线粒体肿胀的动力学，从而深入了解介导线粒体肿胀的机制。利用参数估计技术计算模型参数的值，并通过拟合分析模型与实验数据之间的最小平均差值来验证模型。这些方法将迭代地提高模型的预测精度。线粒体基质体积的调节可以缓解压力，从而使线粒体保持其功能和形态的完整性，有助于维持细胞生命。从简单的动力学模型到复杂模型的发展将考虑线粒体离子扩散动力学、动力学因素、膜电位和膜力学特性，并为新开发的数学工具应用于细胞内其他模型分析提供坚实的基础。该模型将考虑由膨胀过程引起的膜中的非线性机械应力，这是线粒体行为建模的一个重要因素。机械应力参数将描述膜衰变，并涵盖可逆和不可逆线粒体肿胀。准确估计由可逆膨胀向不可逆膨胀过渡的阈值参数对于理解细胞死亡的机制非常重要。该项目由分子和细胞生物学部门以及刺激竞争研究的既定计划（EPSCoR）共同资助。该奖项反映了美国国家科学基金会的法定使命，并通过使用基金会的知识价值和更广泛的影响审查标准进行评估，被认为值得支持。

Mitochondria are the “power plants” of cells, providing ATP for myriad processes. The inner mitochondrial membrane (IMM) is essential for ATP production and plays a critical role in maintaining the volume of this organelle. Small reversible changes in the volume are associated with regulation of mitochondrial function, whereas large irreversible changes result in mitochondrial dysfunction and even cell death. The primary mechanism of excessive mitochondrial swelling includes the opening of channels known as permeability transition pores. The mechanisms underlying the transition from the reversible to irreversible swelling remain unclear. What intra- and extramitochondrial factors are involved in swelling? How the physical and chemical characteristics of the IMM coordinate this process? The multiscale biophysical modeling proposed in this project will characterize mitochondrial swelling throughout all its phases and, thus, describe the mechanisms of transition from the reversible to irreversible swelling. The project will develop a more comprehensive model of this fundamental biological process by application of a wide range of experimental and modeling approaches. The Broader Impact activities will include the training of students in quantitative analysis and modeling approaches.The main goal of this project is to develop a comprehensive model of mitochondrial swelling based on the kinetics of ions and neutral species through the IMM and the mechanical characteristics of the membrane. The project aims to provide an in-depth understanding of the mechanisms that mediate mitochondrial swelling by developing a biophysical multiscale model to simulate and predict the dynamics of mitochondrial swelling. The values of modeling parameters will be calculated using parameter estimation techniques, and the model will be verified and validated by fitting analysis of the minimum average differences between the model and the experimental data. These approaches will iteratively improve the predictive accuracy of the model. The regulation of the mitochondrial matrix volume can provide relief to stress, thus allowing mitochondria to maintain their functional and morphological integrity, aiding in sustaining cellular life. The development of the in silico modeling from a simple kinetic model to a complex model will take into consideration the dynamics of mitochondrial ion diffusion, kinetic factors, membrane potential, and membrane mechanical properties and provide a solid foundation for application of new developed mathematical tools to other model analyses in the cell. The model will consider nonlinear mechanical stress in membranes induced by a swelling process, which is an important factor in the modeling of mitochondria behavior. The mechanical stress parameters will describe membrane decay and cover both reversible and irreversible mitochondrial swelling. Accurate estimation of the threshold parameters for the transition of the reversible to the irreversible swelling is important for understanding the mechanisms of cell death.This project is jointly funded by the Division of Molecular and Cellular Biology, along with the Established Program to Stimulate Competitive Research (EPSCoR).This award reflects NSF's statutory mission and has been deemed worthy of support through evaluation using the Foundation's intellectual merit and broader impacts review criteria.