Multi-level modelling of mitochondrial energy metabolism

The cells that make up our bodies themselves contain smaller structures that carry out specific tasks in the cell. The mitochondria are one of these components, and they are the main site in the cell where the oxygen that we breathe is used and the carbon dioxide is produced. As part of this process they generate most of the cell's energy and send it out in the form of the chemical ATP for the rest of the cell to use. It is possible to isolate working mitochondria from cells and to study them in the laboratory, so we know a lot about what substances they take up from the cell and how they are used in energy production. Mitochondria can also be taken apart, and we now have detailed knowledge of the components they are built from and the enzymes that bring about the energy production. What remains difficult is building a detailed description of how mitochondria work in the cell from all these isolated bits and pieces. The purpose of this project is to make computer models that will help us to do this. Understanding how mitochondria work is important in itself, but they can develop faults that cause a number of diseases, so the models will also help to understand these diseases better, and maybe help to design treatments.

The following is reduced from the longer summary (4000 chars allowed) in the main document. This project adopts a multi-level modelling approach to mitochondrial energy metabolism that uses an appropriate modelling technique for each level, but that makes explicit the quantitative and qualitative interactions with adjacent levels. The modelling is supported by a substantial body of data already collected and additional experiments will be carried out to help refine model structure and parameter estimates, and to test model predictions. The redox reactions of respiratory chain components in the inner mitochondrial/cristal membrane will be modelled by a stochastic, multui-agent simulation approach, with probabilities of reaction being dependent on the 3D geometry of the interacting molecules. A coarse-grained modelling approach will be adopted to model the interactions between complexes embedded in the membrane. The middle metabolic level will be modelled deterministically using empirical, approximate enzyme rate equations that will include terms for the protonmotive force. The reactions of oxidative phosphorylation will be interfaced to the major metabolic pathways and metabolite shuttles in the mitochondria. Multi-agent and PDE approach will be used to model the dynamics of the mitochondrial network in the cell resulting from the opposing tendencies of fusion and fission. The outcomes will include a complete stochastic model of mitochondrial oxidative phosphorylation; In addition, linked models across the levels will be able to account for: the different characteristics of mitochondria from different tissues, including the differing flux control coefficients of the same complex in different tissues; the selection of different oxidizable substrates by the respiratory chain, and the effects of certain mutations in the respiratory complexes on energy metabolism, including the tissue specificity of these effects and the consequences on mitochondrial diseases