Van Eunen 2013 PLoS Comput Biol
van Eunen K, Simons SM, Gerding A, Bleeker A, den Besten G, Touw CM, Houten SM, Groen BK, Krab K, Reijngoud DJ, Bakker BM (2013) Biochemical competition makes fatty-acid Ξ²-oxidation vulnerable to substrate overload. PLoS Comput Biol 9:e1003186. |
van Eunen K, Simons SM, Gerding A, Bleeker A, den Besten G, Touw CM, Houten SM, Groen BK, Krab K, Reijngoud DJ, Bakker BM (2013) PLoS Comput Biol
Abstract: Fatty-acid metabolism plays a key role in acquired and inborn metabolic diseases. To obtain insight into the network dynamics of fatty-acid Ξ²-oxidation, we constructed a detailed computational model of the pathway and subjected it to a fat overload condition. The model contains reversible and saturable enzyme-kinetic equations and experimentally determined parameters for rat-liver enzymes. It was validated by adding palmitoyl CoA or palmitoyl carnitine to isolated rat-liver mitochondria: without refitting of measured parameters, the model correctly predicted the Ξ²-oxidation flux as well as the time profiles of most acyl-carnitine concentrations. Subsequently, we simulated the condition of obesity by increasing the palmitoyl-CoA concentration. At a high concentration of palmitoyl CoA the Ξ²-oxidation became overloaded: the flux dropped and metabolites accumulated. This behavior originated from the competition between acyl CoAs of different chain lengths for a set of acyl-CoA dehydrogenases with overlapping substrate specificity. This effectively induced competitive feedforward inhibition and thereby led to accumulation of CoA-ester intermediates and depletion of free CoA (CoASH). The mitochondrial [NADβΊ]/[NADH] ratio modulated the sensitivity to substrate overload, revealing a tight interplay between regulation of Ξ²-oxidation and mitochondrial respiration.
β’ O2k-Network Lab: NL Groningen Reijngoud RJ
Labels: MiParea: Respiration
Pathology: Obesity
Stress:Mitochondrial disease
Organism: Rat
Tissue;cell: Liver
Preparation: Isolated mitochondria
Regulation: Fatty acid Coupling state: OXPHOS Pathway: F, N HRR: Oxygraph-2k
Labels, 2017-01