ArticlePLoS computational biology2013
Biochemical competition makes fatty-acid β-oxidation vulnerable to substrate overload.
Article in PLoS computational biology, 2013. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 33 papers.
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Who cites it
33 citing papers in PubMed.
- Integrative simulation analysis of myocardial ischaemia-reperfusion injury.The Journal of physiology · 2026Article
- Energetic stress in combination with impaired fatty acid oxidation induces sequestration of CoA and adaptation of CoA metabolism.The FEBS journal · 2026Article
- Continuous multi-omics pathway enrichment analysis resolves hidden functional heterogeneity.Briefings in bioinformatics · 2026Article
- SWATH-MS insights on sodium butyrate effect on mAbs production and redox homeostasis in CHO cells.AMB Express · 2024Article
- Personalised modelling of clinical heterogeneity between medium-chain acyl-CoA dehydrogenase patients.BMC biology · 2023Article
- Kinetic data for modeling the dynamics of the enzymes involved in animal fatty acid synthesis.Bioscience reports · 2023Review
- Mitochondrial reprogramming in peripheral blood mononuclear cells of patients with glycogen storage disease type Ia.Genes & nutrition · 2023Article
- Pyruvate-supported flux through medium-chain ketothiolase promotes mitochondrial lipid tolerance in cardiac and skeletal muscles.Cell metabolism · 2023Article
- Body mass index associates with amyotrophic lateral sclerosis survival and metabolomic profiles.Muscle & nerve · 2023Article
- Metabolomics identifies shared lipid pathways in independent amyotrophic lateral sclerosis cohorts.Brain : a journal of neurology · 2022Article
- Serum lipidomic determinants of human diabetic neuropathy in type 2 diabetes.Annals of clinical and translational neurology · 2022Article
- Bistability in fatty-acid oxidation resulting from substrate inhibition.PLoS computational biology · 2021Article
- Murine deficiency of peroxisomal L-bifunctional protein (EHHADH) causes medium-chain 3-hydroxydicarboxylic aciduria and perturbs hepatic cholesterol homeostasis.Cellular and molecular life sciences : CMLS · 2021Article
- Exacerbation of myopathy triggered by antiobesity drugs in a patient with multiple acyl-CoA dehydrogenase deficiency.BMC neurology · 2021Article
- Metabolic and Energy Imbalance in Dysglycemia-Based Chronic Disease.Diabetes, metabolic syndrome and obesity : targets and therapy · 2021Review
- Multiple mitochondrial thioesterases have distinct tissue and substrate specificity and CoA regulation, suggesting unique functional roles.The Journal of biological chemistry · 2019Article
- Complex I is bypassed during high intensity exercise.Nature communications · 2019Article
- Transcriptome analysis suggests a compensatory role of the cofactors coenzyme A and NADScientific reports · 2019Article
- Calorie restriction reprograms diurnal rhythms in protein translation to regulate metabolism.FASEB journal : official publication of the Federation of American Societies for Experimental Biology · 2019Article
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11 authors.
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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.
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