title: Dynamic simulations on the mitochondrial fatty acid beta-oxidation network.
abstract: BACKGROUND
  The oxidation of fatty acids in mitochondria plays an important role in energy metabolism and genetic disorders of this pathway may cause metabolic diseases. Enzyme deficiencies can block the metabolism at defined reactions in the mitochondrion and lead to accumulation of specific substrates causing severe clinical manifestations. Ten of the disorders directly affecting mitochondrial fatty acid oxidation have been well-defined, implicating episodic hypoketotic hypoglycemia provoked by catabolic stress, multiple organ failure, muscle weakness, or hypertrophic cardiomyopathy. Additionally, syndromes of severe maternal illness (HELLP syndrome and AFLP) have been associated with pregnancies carrying a fetus affected by fatty acid oxidation deficiencies. However, little is known about fatty acids kinetics, especially during fasting or exercise when the demand for fatty acid oxidation is increased (catabolic stress).
  
  
  RESULTS
  A computational kinetic network of 64 reactions with 91 compounds and 301 parameters was constructed to study dynamic properties of mitochondrial fatty acid beta-oxidation. Various deficiencies of acyl-CoA dehydrogenase were simulated and verified with measured concentrations of indicative metabolites of screened newborns in Middle Europe and South Australia. The simulated accumulation of specific acyl-CoAs according to the investigated enzyme deficiencies are in agreement with experimental data and findings in literature. Investigation of the dynamic properties of the fatty acid beta-oxidation reveals that the formation of acetyl-CoA - substrate for energy production - is highly impaired within the first hours of fasting corresponding to the rapid progress to coma within 1-2 hours. LCAD deficiency exhibits the highest accumulation of fatty acids along with marked increase of these substrates during catabolic stress and the lowest production rate of acetyl-CoA. These findings might confirm gestational loss to be the explanation that no human cases of LCAD deficiency have been described.
  
  
  CONCLUSIONS
  In summary, this work provides a detailed kinetic model of mitochondrial metabolism with specific focus on fatty acid beta-oxidation to simulate and predict the dynamic response of that metabolic network in the context of human disease. Our findings offer insight into the disease process (e.g. rapid progress to coma) and might confirm new explanations (no human cases of LCAD deficiency), which can hardly be obtained from experimental data alone.
authors.affiliation: eHealth systems, Biomedical Engineering, Austrian Research Centers GmbH - ARC, Eduard Wallnoefer Zentrum 1, 6060 Hall in Tirol, Austria. robert.modre@arcsmed.at
authors.forename: Robert
authors.initials: R
authors.lastname: Modre-Osprian
authors.forename: Ingrid
authors.initials: I
authors.lastname: Osprian
authors.forename: Bernhard
authors.initials: B
authors.lastname: Tilg
authors.forename: Günter
authors.initials: G
authors.lastname: Schreier
authors.forename: Klaus M
authors.initials: KM
authors.lastname: Weinberger
authors.forename: Armin
authors.initials: A
authors.lastname: Graber
mesh_terms: D044944:Acyl-CoA Dehydrogenases / Q000172:deficiency / Q000235:genetics; D004734:Energy Metabolism; D005215:Fasting / Q000378:metabolism; D005227:Fatty Acids / Q000378:metabolism*; D005260:Female; D006801:Humans; D007231:Infant, Newborn; D007700:Kinetics; D053858:Metabolic Networks and Pathways; D008928:Mitochondria / Q000378:metabolism*; D028361:Mitochondrial Diseases / Q000201:enzymology / Q000235:genetics; D008954:Models, Biological; D010084:Oxidation-Reduction; D011247:Pregnancy; D049490:Systems Biology
chemical_list: D005227:Fatty Acids; D044944:Acyl-CoA Dehydrogenases