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

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

doi:10.1186/s12915-016-0327-5

Abstract

BackgroundDefects 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.ResultsFirst, 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.ConclusionWe 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.Electronic supplementary materialThe online version of this article (doi:10.1186/s12915-016-0327-5) contains supplementary material, which is available to authorized users.

Highlights

Defects in genes involved in mitochondrial fatty-acid oxidation 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
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, in the absence of medium-chain acyl-CoA dehydrogenase (MCAD); (2) this substrate competition is physiologically relevant since it is a key factor in explaining the patientspecific acylcarnitine profiles of multiple acyl-CoA dehydrogenase deficiency (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 activity was measured with phenylpropionyl-CoA as a supposedly MCAD-specific substrate

Summary

Introduction

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. Defects in genes involved in mitochondrial fatty-acid oxidation (mFAO) reduce the ability of patients to cope with metabolic challenges. More than 15 different inborn errors of metabolism have been described in this pathway These genetic disorders affect organs such as the liver, heart and skeletal muscle [1], and together they. The clinical manifestations of mFAO disorders can be aggravated by fasting, exposure to cold, or exercise [7, 8] Such circumstances may lead to sudden death, biochemically associated with hypoketotic hypoglycemia, even in patients with the apparently mild MCAD deficiency. The link between this shortage of amino acids and the primary enzyme defect in mFAO is still unclear This illustrates that, the enzymes involved in mFAO are well known, our understanding of the regulation of this pathway is far from complete. Further insights into mFAO functioning will help to improve the treatment of patients with inherited mFAO disorders, but should contribute to a better understanding of how the mFAO pathway is involved in multifactorial and age-related diseases, such as obesity and type 2 diabetes [10]

Methods

Results

Discussion

Conclusion