title: Flux-balance analysis of mitochondrial energy metabolism: consequences of systemic stoichiometric constraints.
abstract: Mitochondrial metabolism is a critical component in the functioning and maintenance of cellular organs. The stoichiometry of biochemical reaction networks imposes constraints on mitochondrial function. A modeling framework, flux-balance analysis (FBA), was used to characterize the optimal flux distributions for maximal ATP production in the mitochondrion. The model predicted the expected ATP yields for glucose, lactate, and palmitate. Genetic defects that affect mitochondrial functions have been implicated in several human diseases. FBA can characterize the metabolic behavior due to genetic deletions at the metabolic level, and the effect of mutations in the tricarboxylic acid (TCA) cycle on mitochondrial ATP production was simulated. The mitochondrial ATP production is severely affected by TCA-cycle mutations. In addition, the model predicts the secretion of TCA-cycle intermediates, which is observed in clinical studies of mitochondriopathies such as those associated with fumarase deficiency. The model provides a systemic perspective to characterize the effect of stoichiometric constraints and specific metabolic fluxes on mitochondrial function.
authors.affiliation: Department of Bioengineering, University of California San Diego, La Jolla, California 92093-0412, USA.
authors.forename: R
authors.initials: R
authors.lastname: Ramakrishna
authors.forename: J S
authors.initials: JS
authors.lastname: Edwards
authors.forename: A
authors.initials: A
authors.lastname: McCulloch
authors.forename: B O
authors.initials: BO
authors.lastname: Palsson
mesh_terms: D000255:Adenosine Triphosphate / Q000096:biosynthesis; D001224:Aspartic Acid / Q000378:metabolism; D002952:Citric Acid Cycle / Q000235:genetics; D004734:Energy Metabolism; D005230:Fatty Acids, Nonesterified / Q000378:metabolism; D005182:Flavin-Adenine Dinucleotide / Q000378:metabolism; D005649:Fumarate Hydratase / Q000172:deficiency / Q000235:genetics; D017353:Gene Deletion; D005947:Glucose / Q000378:metabolism; D005994:Glycerophosphates / Q000378:metabolism; D006019:Glycolysis; D006801:Humans; D019344:Lactic Acid / Q000378:metabolism; D008293:Malates / Q000378:metabolism; D008928:Mitochondria / Q000378:metabolism*; D008954:Models, Biological; D009154:Mutation; D009243:NAD / Q000378:metabolism; D010101:Oxygen Consumption; D019308:Palmitic Acid / Q000378:metabolism; D010732:Phosphofructokinase-1 / Q000378:metabolism; D011768:Pyruvate Dehydrogenase Complex / Q000378:metabolism
chemical_list: D005230:Fatty Acids, Nonesterified; D005994:Glycerophosphates; D008293:Malates; D011768:Pyruvate Dehydrogenase Complex; D009243:NAD; D005182:Flavin-Adenine Dinucleotide; D019308:Palmitic Acid; D001224:Aspartic Acid; D019344:Lactic Acid; C030298:malic acid; D000255:Adenosine Triphosphate; D010732:Phosphofructokinase-1; D005649:Fumarate Hydratase; D005947:Glucose