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 β-oxidation vulnerable to substrate overload. PLoS Comput Biol 9:e1003186.|
Abstract: Fatty-acid metabolism plays a key role in acquired and inborn metabolic diseases. To obtain insight into the network dynamics of fatty-acid β-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 β-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 β-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 [NAD⁺]/[NADH] ratio modulated the sensitivity to substrate overload, revealing a tight interplay between regulation of β-oxidation and mitochondrial respiration.
• O2k-Network Lab: NL Groningen Reijngoud RJ
Labels: MiParea: Respiration Pathology: Obesity
Organism: Rat Tissue;cell: Liver Preparation: Isolated mitochondria
Regulation: Fatty acid Coupling state: ET Pathway: F, N HRR: Oxygraph-2k
- Malonyl-CoA inhibits carnitine acyltransferase (in Fig1 scheme).
- Computer model to predict interaction and disturbances in beta-oxidation pathways. It is a cycle phenomenon and you have to reduce fatty acids 2 carbons at a time, leading to multiple fraction that repeat the same enzymatic pathway. This repetition could lead to inhibition due to lack of different enzymes for different carbon lengths.
- In pathological conditions, FAO could be impaired due to overload of acyl-CoA, lack of “free” CoA leading to lower beta-oxidation. However there might be some protective mechanisms that could prevent this phenomenon, presence of Malonyl-CoA preventing conversion of fatty acids into acylcarnitines to be transported to the mitochondria.
- However, despite having a good prediction of behavior, much still has to be improved to confirm the precision of this model.
- “Mitochondria were incubated with an excess amount of malate. In this way CoASH could be regenerated from acetyl CoA by malate dehydrogenase and citrate synthase, allowing the boxidation to proceed. Each cycle of b-oxidation in the presence of excess malate gives rise to 1 FADH2 by acyl-CoA dehydrogenase and 2 NADH by enoyl-CoA dehydrogenase and malate dehydrogenase.”
- “We found that the unique pathway structure makes the FA boxidation vulnerable to substrate overload: at high palmitoyl-CoA concentrations the shorter CoA esters accumulate to outcompete the palmitoyl CoA. Above a critical palmitoyl-CoA concentration this results in depletion of CoASH and a steep decline in flux.”