High-Quality Reconstruction of Human Synaptic and Asynaptic Mitochondrial Metabolic Networks Based on Predefined Metabolic Sets of Reactions

Considering the high energy demand of the complex axonal arborisation of dopaminergic neurons, reduced ATP synthesis could lead to an imbalance between supply and demand, thereby creating an inability to sustain normal neuronal bioenergetic requirements and increase vulnerability to degeneration. Conversely, in comparison to other neurons, it has been described that dopaminergic neurons in the substantia nigra seem to contain a lower mitochondrial mass, potentially contributing to their increased vulnerability to degeneration in Parkinson's disease. A systems biology approach is required to identify the metabolic pathways used by dopaminergic neuronal mitochondria for energy generation. By combining the existing mitochondrial component of Recon 2 with manual curation of the biochemical literature, reconstructions of synaptic and asynaptic mitochondrial metabolism were generated. Where biochemical data on human dopaminergic neurons was absent, extrapolated data from non-human mammals (e.g. rodents) was used. This reconstruction effort is aimed toward the generation of an accurate, comprehensive, constraint-based model of dopaminergic neuronal metabolism with a view toward discovery of novel neuroprotectants, by selection of candidate compounds for in vitro screens for neuroprotective efficacy.