Abstract
Swelling of mitochondria plays an important role in the pathogenesis of human diseases by stimulating mitochondria-mediated cell death through apoptosis, necrosis, and autophagy. Changes in the permeability of the inner mitochondrial membrane (IMM) of ions and other substances induce an increase in the colloid osmotic pressure, leading to matrix swelling. Modeling of mitochondrial swelling is important for simulation and prediction of in vivo events in the cell during oxidative and energy stress. In the present study, we developed a computational model that describes the mechanism of mitochondrial swelling based on osmosis, the rigidity of the IMM, and dynamics of ionic/neutral species. The model describes a new biophysical approach to swelling dynamics, where osmotic pressure created in the matrix is compensated for by the rigidity of the IMM, i.e., osmotic pressure induces membrane deformation, which compensates for the osmotic pressure effect. Thus, the effect is linear and reversible at small membrane deformations, allowing the membrane to restore its normal form. On the other hand, the membrane rigidity drops to zero at large deformations, and the swelling becomes irreversible. As a result, an increased number of dysfunctional mitochondria can activate mitophagy and initiate cell death. Numerical modeling analysis produced results that reasonably describe the experimental data reported earlier.
Highlights
Mitochondria are widely accepted as the powerhouse and provide up to 90% of the ATP necessary for the cell
Molecules 2018, 23, 783 mitochondria-mediated cell death involves excessive matrix swelling induced by the opening of the non-selective channels, permeability transition pores (PTP) in the inner mitochondrial membrane (IMM) [4,5,6] (Figure 1)
We further develop modeling analysis including the transport dynamics of different ions and species across the IMM, and their effects on matrix metabolism, with the objective to describe mitochondrial swelling based on detailed physical and chemical characteristics
Summary
Mitochondria are widely accepted as the powerhouse and provide up to 90% of the ATP necessary for the cell. Molecules 2018, 23, 783 mitochondria-mediated cell death involves excessive matrix swelling induced by the opening of the non-selective channels, permeability transition pores (PTP) in the IMM [4,5,6] (Figure 1). We further develop modeling analysis including the transport dynamics of different ions and species across the IMM, and their effects on matrix metabolism, with the objective to describe mitochondrial swelling based on detailed physical and chemical characteristics. Our modeling approach is based on the experimental data reported earlier by different authors It includes the mechanism of matrix swelling, where the IMM rigidity is described by the rigidity tensor, its components dependent on the IMM deformation scale. We plan to include a description of irreversible swelling in the more complex models with all of the relevant species, which currently disregard the possibility of irreversible swelling
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