A metabolic model of the mitochondrion and its use in modelling diseases of the tricarboxylic acid cycle.

TitleA metabolic model of the mitochondrion and its use in modelling diseases of the tricarboxylic acid cycle.
Publication TypeJournal Article
Year of Publication2011
AuthorsSmith, AC, Robinson, AJ
JournalBMC Syst Biol
Volume5
Pagination102
Date Published2011
ISSN1752-0509
KeywordsCitric Acid Cycle, Fumarate Hydratase, Humans, Ketoglutarate Dehydrogenase Complex, Mitochondria, Mitochondrial Diseases, Models, Biological, Myocytes, Cardiac, Succinate Dehydrogenase
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.CONCLUSION: 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.

DOI10.1186/1752-0509-5-102
Alternate JournalBMC Syst Biol
Citation Key10.1186/1752-0509-5-102
PubMed ID21714867
PubMed Central IDPMC3152903
Grant ListMC_U105674181 / / Medical Research Council / United Kingdom
/ / Medical Research Council / United Kingdom