title: Living on the edge: substrate competition explains loss of robustness in mitochondrial fatty-acid oxidation disorders.
abstract: Defects in genes involved in mitochondrial fatty-acid oxidation (mFAO) reduce the ability of patients to cope with metabolic challenges. mFAO enzymes accept multiple substrates of different chain length, leading to molecular competition among the substrates. Here, we combined computational modeling with quantitative mouse and patient data to investigate whether substrate competition affects pathway robustness in mFAO disorders.
  
  
  
  First, we used comprehensive biochemical analyses of wild-type mice and mice deficient for medium-chain acyl-CoA dehydrogenase (MCAD) to parameterize a detailed computational model of mFAO. Model simulations predicted that MCAD deficiency would have no effect on the pathway flux at low concentrations of the mFAO substrate palmitoyl-CoA. However, high concentrations of palmitoyl-CoA would induce a decline in flux and an accumulation of intermediate metabolites. We proved computationally that the predicted overload behavior was due to substrate competition in the pathway. Second, to study the clinical relevance of this mechanism, we used patients' metabolite profiles and generated a humanized version of the computational model. While molecular competition did not affect the plasma metabolite profiles during MCAD deficiency, it was a key factor in explaining the characteristic acylcarnitine profiles of multiple acyl-CoA dehydrogenase deficient patients. The patient-specific computational models allowed us to predict the severity of the disease phenotype, providing a proof of principle for the systems medicine approach.
  
  
  
  We conclude that substrate competition is at the basis of the physiology seen in patients with mFAO disorders, a finding that may explain why these patients run a risk of a life-threatening metabolic catastrophe.
authors.affiliation: Department of Pediatrics, University of Groningen, University Medical Center Groningen, Hanzeplein 1, 9713 GZ, Groningen, The Netherlands.|Top Institute for Food and Nutrition, Nieuwe Kanaal 9A, 7609 PA, Wageningen, The Netherlands.
authors.forename: Karen
authors.initials: K
authors.lastname: van Eunen
authors.affiliation: Department of Pediatrics, University of Groningen, University Medical Center Groningen, Hanzeplein 1, 9713 GZ, Groningen, The Netherlands.|Present address: Department of Medical Genetics, University Medical Center Utrecht, Utrecht, The Netherlands.
authors.forename: Catharina M L
authors.initials: CM
authors.lastname: Volker-Touw
authors.affiliation: Department of Pediatrics, University of Groningen, University Medical Center Groningen, Hanzeplein 1, 9713 GZ, Groningen, The Netherlands.
authors.forename: Albert
authors.initials: A
authors.lastname: Gerding
authors.affiliation: Department of Pediatrics, University of Groningen, University Medical Center Groningen, Hanzeplein 1, 9713 GZ, Groningen, The Netherlands.|Top Institute for Food and Nutrition, Nieuwe Kanaal 9A, 7609 PA, Wageningen, The Netherlands.
authors.forename: Aycha
authors.initials: A
authors.lastname: Bleeker
authors.affiliation: Department of Pediatrics, University of Groningen, University Medical Center Groningen, Hanzeplein 1, 9713 GZ, Groningen, The Netherlands.|Analytical Biochemistry and Interfaculty Mass Spectrometry Center, University of Groningen, A. Deusinglaan 1, 9713 AV, Groningen, The Netherlands.
authors.forename: Justina C
authors.initials: JC
authors.lastname: Wolters
authors.affiliation: Section of Metabolic Diseases, Beatrix Children's Hospital, University of Groningen, University Medical Center Groningen, Hanzeplein 1, 9713 GZ, Groningen, The Netherlands.
authors.forename: Willemijn J
authors.initials: WJ
authors.lastname: van Rijt
authors.affiliation: Department of Pediatrics, University of Groningen, University Medical Center Groningen, Hanzeplein 1, 9713 GZ, Groningen, The Netherlands.
authors.forename: Anne-Claire M F
authors.initials: AM
authors.lastname: Martines
authors.affiliation: Department of Laboratory Medicine, University of Groningen, University Medical Center Groningen, Hanzeplein 1, 9713 GZ, Groningen, The Netherlands.
authors.forename: Klary E
authors.initials: KE
authors.lastname: Niezen-Koning
authors.affiliation: Department of Laboratory Medicine, University of Groningen, University Medical Center Groningen, Hanzeplein 1, 9713 GZ, Groningen, The Netherlands.
authors.forename: Rebecca M
authors.initials: RM
authors.lastname: Heiner
authors.affiliation: Analytical Biochemistry and Interfaculty Mass Spectrometry Center, University of Groningen, A. Deusinglaan 1, 9713 AV, Groningen, The Netherlands.
authors.forename: Hjalmar
authors.initials: H
authors.lastname: Permentier
authors.affiliation: Department of Pediatrics, University of Groningen, University Medical Center Groningen, Hanzeplein 1, 9713 GZ, Groningen, The Netherlands.|Department of Laboratory Medicine, University of Groningen, University Medical Center Groningen, Hanzeplein 1, 9713 GZ, Groningen, The Netherlands.|Top Institute for Food and Nutrition, Nieuwe Kanaal 9A, 7609 PA, Wageningen, The Netherlands.|Systems Biology Center for Energy Metabolism and Aging, University of Groningen, University Medical Center Groningen, A. Deusinglaan 1, 9713 AV, Groningen, The Netherlands.
authors.forename: Albert K
authors.initials: AK
authors.lastname: Groen
authors.affiliation: Department of Pediatrics, University of Groningen, University Medical Center Groningen, Hanzeplein 1, 9713 GZ, Groningen, The Netherlands.|Systems Biology Center for Energy Metabolism and Aging, University of Groningen, University Medical Center Groningen, A. Deusinglaan 1, 9713 AV, Groningen, The Netherlands.
authors.forename: Dirk-Jan
authors.initials: DJ
authors.lastname: Reijngoud
authors.affiliation: Section of Metabolic Diseases, Beatrix Children's Hospital, University of Groningen, University Medical Center Groningen, Hanzeplein 1, 9713 GZ, Groningen, The Netherlands.
authors.forename: Terry G J
authors.initials: TG
authors.lastname: Derks
authors.affiliation: Department of Pediatrics, University of Groningen, University Medical Center Groningen, Hanzeplein 1, 9713 GZ, Groningen, The Netherlands. b.m.bakker01@umcg.nl.|Systems Biology Center for Energy Metabolism and Aging, University of Groningen, University Medical Center Groningen, A. Deusinglaan 1, 9713 AV, Groningen, The Netherlands. b.m.bakker01@umcg.nl.|, PO Box 196, Internal ZIP code EA12, NL-9700 AD, Groningen, The Netherlands. b.m.bakker01@umcg.nl.
authors.forename: Barbara M
authors.initials: BM
authors.lastname: Bakker
mesh_terms: D042964:Acyl-CoA Dehydrogenase / Q000172:deficiency* / Q000235:genetics / Q000378:metabolism; D000818:Animals; D002331:Carnitine / Q000031:analogs & derivatives / Q000378:metabolism; D019295:Computational Biology; D003198:Computer Simulation; D004195:Disease Models, Animal; D005227:Fatty Acids / Q000378:metabolism; D006801:Humans; D050356:Lipid Metabolism / Q000235:genetics*; D008052:Lipid Metabolism, Inborn Errors / Q000235:genetics* / Q000378:metabolism; D008297:Male; D053858:Metabolic Networks and Pathways; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008928:Mitochondria / Q000378:metabolism*; D010084:Oxidation-Reduction; D040901:Proteomics; D013379:Substrate Specificity
chemical_list: D005227:Fatty Acids; C116917:acylcarnitine; D042964:Acyl-CoA Dehydrogenase; D002331:Carnitine
keywords: Kinetic modeling; Medium-chain acyl-CoA dehydrogenase deficiency; Mitochondrial fatty-acid oxidation; Multiple acyl-CoA dehydrogenase deficiency; Systems medicine