Biophysical multiscale modeling of mitochondrial swelling

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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.