Living on the edge: substrate competition explains loss of robustness in mitochondrial fatty-acid oxidation disorders

• Published in: BMC biology Vol. 14; no. 1; p. 107
• Main Authors: van Eunen, Karen, Volker-Touw, Catharina M L, Gerding, Albert, Bleeker, Aycha, Wolters, Justina C, van Rijt, Willemijn J, Martines, Anne-Claire M F, Niezen-Koning, Klary E, Heiner, Rebecca M, Permentier, Hjalmar, Groen, Albert K, Reijngoud, Dirk-Jan, Derks, Terry G J, Bakker, Barbara M
• Format: Journal Article
• Language: English
• Published: England BioMed Central Ltd 07.12.2016; BioMed Central
• Subjects: Acyl-CoA Dehydrogenase - deficiency; Acyl-CoA Dehydrogenase - genetics; Acyl-CoA Dehydrogenase - metabolism; Analysis; Animals; Biology; Carnitine - analogs & derivatives; Carnitine - metabolism; Computational Biology; Computer Simulation; Computer-generated environments; Disease Models, Animal; Fatty Acids - metabolism; Humans; Lipid Metabolism - genetics; Lipid Metabolism, Inborn Errors - genetics; Lipid Metabolism, Inborn Errors - metabolism; Male; Metabolic Networks and Pathways; Mice; Mice, Inbred C57BL; Mice, Knockout; Mitochondria - metabolism; Muscles; Oxidation-Reduction; Oxidation-reduction reaction; Physiological aspects; Proteomics; Substrate Specificity; Multiple acyl-CoA dehydrogenase deficiency; Kinetic modeling; Mitochondrial fatty-acid oxidation; Systems medicine; Medium-chain acyl-CoA dehydrogenase deficiency
• ISSN: 1741-7007; 1741-7007
• DOI: 10.1186/s12915-016-0327-5

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.