Patrick Schrauwen

Projects: HUMET Startup

Institutions: University Maastricht

https://orcid.org/0000-0002-0973-847X
Matthias König project_administratorasset_housekeeperasset_gatekeeper

Projects: Kinetics on the move - Workshop 2016, Multi-Scale Models for Personalized Liver Function Tests (LiSyM-MM-PLF), FAIRDOM user meeting, COMBINE Multicellular Modelling, FAIRDOM & LiSyM & de.NBI Data Structuring Training

Institutions: Charité University Medicine Berlin, Humboldt-Universität zu Berlin, Humboldt University Berlin

https://orcid.org/0000-0003-1725-179X
Living on the edge: substrate competition explains loss of robustness in mitochondrial fatty-acid oxidation disorders.
FAIRDOM

Abstract (Expand)

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.

Authors: Karen Van Eunen, C. M. Volker-Touw, A. Gerding, A. Bleeker, J. C. Wolters, W. J. van Rijt, A. M. Martines, K. E. Niezen-Koning, R. M. Heiner, H. Permentier, A. K. Groen, D. J. Reijngoud, Terry G.J. Derks, Barbara Bakker

Date Published: 7th Dec 2016

Journal: BMC Biol

A Predictive 3D Multi-Scale Model of Biliary Fluid Dynamics in the Liver Lobule.
Early Metabolic Injury (LiSyM-EMI - Pillar I)

Abstract (Expand)

Bile, the central metabolic product of the liver, is transported by the bile canaliculi network. The impairment of bile flow in cholestatic liver diseases has urged a demand for insights into its … regulation. Here, we developed a predictive 3D multi-scale model that simulates fluid dynamic properties successively from the subcellular to the tissue level. The model integrates the structure of the bile canalicular network in the mouse liver lobule, as determined by high-resolution confocal and serial block-face scanning electron microscopy, with measurements of bile transport by intravital microscopy. The combined experiment-theory approach revealed spatial heterogeneities of biliary geometry and hepatocyte transport activity. Based on this, our model predicts gradients of bile velocity and pressure in the liver lobule. Validation of the model predictions by pharmacological inhibition of Rho kinase demonstrated a requirement of canaliculi contractility for bile flow in vivo. Our model can be applied to functionally characterize liver diseases and quantitatively estimate biliary transport upon drug-induced liver injury.

Authors: K. Meyer, O. Ostrenko, G. Bourantas, H. Morales-Navarrete, N. Porat-Shliom, F. Segovia-Miranda, H. Nonaka, A. Ghaemi, J. M. Verbavatz, Lutz Brusch, I. Sbalzarini, Y. Kalaidzidis, R. Weigert, M. Zerial

Date Published: No date defined

Journal: Cell Syst

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