title: A metabolic model of the mitochondrion and its use in modelling diseases of the tricarboxylic acid cycle.
abstract: BACKGROUND
  Mitochondria are a vital component of eukaryotic cells and their dysfunction is implicated in a large number of metabolic, degenerative and age-related human diseases. The mechanism or these disorders can be difficult to elucidate due to the inherent complexity of mitochondrial metabolism. To understand how mitochondrial metabolic dysfunction contributes to these diseases, a metabolic model of a human heart mitochondrion was created.
  
  
  RESULTS
  A new model of mitochondrial metabolism was built on the principle of metabolite availability using MitoMiner, a mitochondrial proteomics database, to evaluate the subcellular localisation of reactions that have evidence for mitochondrial localisation. Extensive curation and manual refinement was used to create a model called iAS253, containing 253 reactions, 245 metabolites and 89 transport steps across the inner mitochondrial membrane. To demonstrate the predictive abilities of the model, flux balance analysis was used to calculate metabolite fluxes under normal conditions and to simulate three metabolic disorders that affect the TCA cycle: fumarase deficiency, succinate dehydrogenase deficiency and α-ketoglutarate dehydrogenase deficiency.
  
  
  CONCLUSIONS
  The results of simulations using the new model corresponded closely with phenotypic data under normal conditions and provided insight into the complicated and unintuitive phenotypes of the three disorders, including the effect of interventions that may be of therapeutic benefit, such as low glucose diets or amino acid supplements. The model offers the ability to investigate other mitochondrial disorders and can provide the framework for the integration of experimental data in future studies.
authors.affiliation: The Medical Research Council, Mitochondrial Biology Unit, Hills Road, Cambridge CB2 0XY, UK.
authors.forename: Anthony C
authors.initials: AC
authors.lastname: Smith
authors.forename: Alan J
authors.initials: AJ
authors.lastname: Robinson
mesh_terms: D002952:Citric Acid Cycle; D005649:Fumarate Hydratase / Q000172:deficiency; D006801:Humans; D007655:Ketoglutarate Dehydrogenase Complex / Q000172:deficiency; D008928:Mitochondria / Q000378:metabolism*; D028361:Mitochondrial Diseases / Q000378:metabolism* / Q000473:pathology; D008954:Models, Biological; D032383:Myocytes, Cardiac / Q000201:enzymology / Q000378:metabolism / Q000473:pathology; D013385:Succinate Dehydrogenase / Q000172:deficiency
chemical_list: D007655:Ketoglutarate Dehydrogenase Complex; D013385:Succinate Dehydrogenase; D005649:Fumarate Hydratase