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4. Transcriptome analysis suggests a compensatory role of the cofactors coenzyme A and NAD+ in medium-chain acyl-CoA dehydrogenase knockout mice

Author

LS Pathobiologie, dPB RMSC, Martines, Anne-Claire M F, Gerding, Albert, Stolle, Sarah, Vieira-Lara, Marcel A, Wolters, Justina C, Jurdzinski, Angelika, Bongiovanni, Laura, de Bruin, Alain, van der Vlies, Pieter, van der Vries, Gerben, Bloks, Vincent W, Derks, Terry G J, Reijngoud, Dirk-Jan, Bakker, Barbara M, LS Pathobiologie, dPB RMSC, Martines, Anne-Claire M F, Gerding, Albert, Stolle, Sarah, Vieira-Lara, Marcel A, Wolters, Justina C, Jurdzinski, Angelika, Bongiovanni, Laura, de Bruin, Alain, van der Vlies, Pieter, van der Vries, Gerben, Bloks, Vincent W, Derks, Terry G J, Reijngoud, Dirk-Jan, and Bakker, Barbara M

Published
2019

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

Author

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., 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, and Bakker, Barbara M.

Published
2016

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

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, 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, and Bakker, Barbara M

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.

Published
2016

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

Author

Genetica Klinische Genetica, Child Health, 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., Genetica Klinische Genetica, Child Health, 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, and Bakker, Barbara M.

Published
2016

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

Author

van Eunen, Karen, primary, Volker-Touw, Catharina M. L., additional, Gerding, Albert, additional, Bleeker, Aycha, additional, Wolters, Justina C., additional, van Rijt, Willemijn J., additional, Martines, Anne-Claire M. F., additional, Niezen-Koning, Klary E., additional, Heiner, Rebecca M., additional, Permentier, Hjalmar, additional, Groen, Albert K., additional, Reijngoud, Dirk-Jan, additional, Derks, Terry G. J., additional, and Bakker, Barbara M., additional

Published
2016
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10. Transcriptome analysis suggests a compensatory role of the cofactors coenzyme A and NAD+ in medium-chain acyl-CoA dehydrogenase knockout mice.

Author

Martines, Anne-Claire M. F., Gerding, Albert, Stolle, Sarah, Vieira-Lara, Marcel A., Wolters, Justina C., Jurdzinski, Angelika, Bongiovanni, Laura, de Bruin, Alain, van der Vlies, Pieter, van der Vries, Gerben, Bloks, Vincent W., Derks, Terry G. J., Reijngoud, Dirk-Jan, and Bakker, Barbara M.

Subjects
TRANSCRIPTOMES, COENZYME A, DEHYDROGENASES, ENZYME deficiency, LABORATORY mice
Abstract

During fasting, mitochondrial fatty-acid β-oxidation (mFAO) is essential for the generation of glucose by the liver. Children with a loss-of-function deficiency in the mFAO enzyme medium-chain acyl-Coenzyme A dehydrogenase (MCAD) are at serious risk of life-threatening low blood glucose levels during fasting in combination with intercurrent disease. However, a subset of these children remains asymptomatic throughout life. In MCAD-deficient (MCAD-KO) mice, glucose levels are similar to those of wild-type (WT) mice, even during fasting. We investigated if metabolic adaptations in the liver may underlie the robustness of this KO mouse. WT and KO mice were given a high- or low-fat diet and subsequently fasted. We analyzed histology, mitochondrial function, targeted mitochondrial proteomics, and transcriptome in liver tissue. Loss of MCAD led to a decreased capacity to oxidize octanoyl-CoA. This was not compensated for by altered protein levels of the short- and long-chain isoenzymes SCAD and LCAD. In the transcriptome, we identified subtle adaptations in the expression of genes encoding enzymes catalyzing CoA- and NAD(P)(H)-involving reactions and of genes involved in detoxification mechanisms. We discuss how these processes may contribute to robustness in MCAD-KO mice and potentially also in asymptomatic human subjects with a complete loss of MCAD activity. [ABSTRACT FROM AUTHOR]

Published
2019
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