Publication

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

van Eunen, K., Volker-Touw, C. M. L., Gerding, A., Bleeker, A., Wolters, J. C., Rijt, van, W., Martines, A-C. M. F., Niezen-Koning, K. E., Heiner, R. M., Permentier, H., Groen, A. K., Reijngoud, D-J., Derks, T. G. J. & Bakker, B. M., 7-Dec-2016, In : BMC Biology. 14, 1, 15 p., 107.

Research output: Contribution to journalArticleAcademicpeer-review

APA

van Eunen, K., Volker-Touw, C. M. L., Gerding, A., Bleeker, A., Wolters, J. C., Rijt, van, W., ... Bakker, B. M. (2016). Living on the edge: substrate competition explains loss of robustness in mitochondrial fatty-acid oxidation disorders. BMC Biology, 14(1), [107]. https://doi.org/10.1186/s12915-016-0327-5

Author

van Eunen, Karen ; Volker-Touw, Catharina M L ; Gerding, Albert ; Bleeker, Aycha ; Wolters, Justina C ; Rijt, van, Willemijn ; 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. / Living on the edge : substrate competition explains loss of robustness in mitochondrial fatty-acid oxidation disorders. In: BMC Biology. 2016 ; Vol. 14, No. 1.

Harvard

van Eunen, K, Volker-Touw, CML, Gerding, A, Bleeker, A, Wolters, JC, Rijt, van, W, Martines, A-CMF, Niezen-Koning, KE, Heiner, RM, Permentier, H, Groen, AK, Reijngoud, D-J, Derks, TGJ & Bakker, BM 2016, 'Living on the edge: substrate competition explains loss of robustness in mitochondrial fatty-acid oxidation disorders', BMC Biology, vol. 14, no. 1, 107. https://doi.org/10.1186/s12915-016-0327-5

Standard

Living on the edge : substrate competition explains loss of robustness in mitochondrial fatty-acid oxidation disorders. / van Eunen, Karen; Volker-Touw, Catharina M L; Gerding, Albert; Bleeker, Aycha; Wolters, Justina C; Rijt, van, Willemijn; 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.

In: BMC Biology, Vol. 14, No. 1, 107, 07.12.2016.

Research output: Contribution to journalArticleAcademicpeer-review

Vancouver

van Eunen K, Volker-Touw CML, Gerding A, Bleeker A, Wolters JC, Rijt, van W et al. Living on the edge: substrate competition explains loss of robustness in mitochondrial fatty-acid oxidation disorders. BMC Biology. 2016 Dec 7;14(1). 107. https://doi.org/10.1186/s12915-016-0327-5


BibTeX

@article{af8e68d5a166477d9c866712db717715,
title = "Living on the edge: substrate competition explains loss of robustness in mitochondrial fatty-acid oxidation disorders",
abstract = "BACKGROUND: 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.RESULTS: 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.CONCLUSION: 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 = "Medium-chain acyl-CoA dehydrogenase deficiency, Multiple acyl-CoA dehydrogenase deficiency, Mitochondrial fatty-acid oxidation, Systems medicine, Kinetic modeling, CHAIN ACYL-COA, MCAD DEFICIENCY, BETA-OXIDATION, DEHYDROGENASE-DEFICIENCY, RAT-LIVER, METABOLISM, COENZYME, NETHERLANDS, ENZYME, PHOSPHORYLATION",
author = "{van Eunen}, Karen and Volker-Touw, {Catharina M L} and Albert Gerding and Aycha Bleeker and Wolters, {Justina C} and {Rijt, van}, Willemijn and Martines, {Anne-Claire M F} and Niezen-Koning, {Klary E.} and Heiner, {Rebecca M.} and Hjalmar Permentier and Groen, {Albert K} and Dirk-Jan Reijngoud and Derks, {Terry G J} and Bakker, {Barbara M}",
year = "2016",
month = "12",
day = "7",
doi = "10.1186/s12915-016-0327-5",
language = "English",
volume = "14",
journal = "BMC Biology",
issn = "1741-7007",
publisher = "BioMed Central Ltd.",
number = "1",

}

RIS

TY - JOUR

T1 - Living on the edge

T2 - substrate competition explains loss of robustness in mitochondrial fatty-acid oxidation disorders

AU - van Eunen, Karen

AU - Volker-Touw, Catharina M L

AU - Gerding, Albert

AU - Bleeker, Aycha

AU - Wolters, Justina C

AU - Rijt, van, Willemijn

AU - Martines, Anne-Claire M F

AU - Niezen-Koning, Klary E.

AU - Heiner, Rebecca M.

AU - Permentier, Hjalmar

AU - Groen, Albert K

AU - Reijngoud, Dirk-Jan

AU - Derks, Terry G J

AU - Bakker, Barbara M

PY - 2016/12/7

Y1 - 2016/12/7

N2 - BACKGROUND: 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.RESULTS: 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.CONCLUSION: 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.

AB - BACKGROUND: 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.RESULTS: 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.CONCLUSION: 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.

KW - Medium-chain acyl-CoA dehydrogenase deficiency

KW - Multiple acyl-CoA dehydrogenase deficiency

KW - Mitochondrial fatty-acid oxidation

KW - Systems medicine

KW - Kinetic modeling

KW - CHAIN ACYL-COA

KW - MCAD DEFICIENCY

KW - BETA-OXIDATION

KW - DEHYDROGENASE-DEFICIENCY

KW - RAT-LIVER

KW - METABOLISM

KW - COENZYME

KW - NETHERLANDS

KW - ENZYME

KW - PHOSPHORYLATION

U2 - 10.1186/s12915-016-0327-5

DO - 10.1186/s12915-016-0327-5

M3 - Article

VL - 14

JO - BMC Biology

JF - BMC Biology

SN - 1741-7007

IS - 1

M1 - 107

ER -

ID: 37791107