Van Eunen 2016 BMC Biol

From Bioblast
Jump to: navigation, search
Publications in the MiPMap
van Eunen K, Volker-Touw CM, Gerding A, Bleeker A, Wolters JC, van Rijt WJ, Martines AM, Niezen-Koning KE, Heiner RM, Permentier H, Groen AK, Reijngoud DJ, Derks TG, Bakker BM (2016) Living on the edge: substrate competition explains loss of robustness in mitochondrial fatty-acid oxidation disorders. BMC Biol 14:107.

» PMID: 27927213 Open Access

van Eunen K, Volker-Touw CM, Gerding A, Bleeker A, Wolters JC, van Rijt WJ, Martines AM, Niezen-Koning KE, Heiner RM, Permentier H, Groen AK, Reijngoud DJ, Derks TG, Bakker BM (2016) BMC Biol

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.

Keywords: Kinetic modeling, Medium-chain acyl-CoA dehydrogenase deficiency, Mitochondrial fatty-acid oxidation, Multiple acyl-CoA dehydrogenase deficiency, Systems medicine

O2k-Network Lab: NL Groningen Reijngoud RJ


Labels: MiParea: Respiration, mtDNA;mt-genetics, Genetic knockout;overexpression 


Organism: Mouse  Tissue;cell: Liver  Preparation: Isolated mitochondria 

Regulation: Substrate, Fatty acid  Coupling state: ET  Pathway: F, N  HRR: Oxygraph-2k 


  1. Summary:
  • Knock-out mice for medium chain acyl-CoA dehydrogenase showed impaired enzyme activity on short and medium chain acyl-CoAs.
  • A computer model, similar to the 2013 publication tries to predict the competition model in FAO metabolism. Once again, the model proves itself reliable and correlatable to FAO pathologies.
  • However, it is brought up to light of the importance of the CoASH pool that could play a bigger role than just substrate competition of Acyl-CoAs ennymes.
  1. Quotes:
  • “Here we provide evidence that (1) substrate competition in mFAO – a mechanism inherent to the repetitive metabolism of fatty acids – renders the pathway vulnerable to substrate overload, particularly in the absence of MCAD; (2) this substrate competition is physiologically relevant since it is a key factor in explaining the patientspecific acylcarnitine profiles of MADD patients; and (3) it is clinically relevant since a computational model that included substrate competition was able to explain the severity of the patients’ symptoms from their acylcarnitine profiles, while a similar model without competition could not.”
  • “The resulting flux decline was mediated by a self-amplifying depletion of CoASH.”
  • “CoASH is an essential cofactor, and the maintenance of the CoASH pool is critical for energy metabolism.”