Pyruvate-supported flux through medium chain ketothiolase promotes mitochondrial lipid tolerance in cardiac and skeletal muscles
Ontology highlight
ABSTRACT:
ORGANISM(S): Mus Musculus (mouse)
SUBMITTER: Deborah M. Muoio
PROVIDER: PXD040326 | JPOST Repository | Fri Apr 14 00:00:00 BST 2023
REPOSITORIES: jPOST
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| 2020-09-01_%2310_PGC1-TG_1ug.raw | Raw | |||
| 2020-09-01_%2311_PGC1-WT_1ug.raw | Raw | |||
| 2020-09-01_%231_PGC1-TG_1ug.raw | Raw | |||
| 2020-09-01_%232_PGC1-TG_1ug.raw | Raw | |||
| 2020-09-01_%233_PGC1-WT_1ug.raw | Raw |
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Publications
Pyruvate-supported flux through medium-chain ketothiolase promotes mitochondrial lipid tolerance in cardiac and skeletal muscles.
Koves Timothy R TR Zhang Guo-Fang GF Davidson Michael T MT Chaves Alec B AB Crown Scott B SB Johnson Jordan M JM Slentz Dorothy H DH Grimsrud Paul A PA Muoio Deborah M DM
Cell metabolism 20230414 6
Even-chain acylcarnitine (AC) metabolites, most of which are generated as byproducts of incomplete fatty acid oxidation (FAO), are viewed as biomarkers of mitochondrial lipid stress attributable to one or more metabolic bottlenecks in the β-oxidation pathway. The origins and functional implications of FAO bottlenecks remain poorly understood. Here, we combined a sophisticated mitochondrial phenotyping platform with state-of-the-art molecular profiling tools and multiple two-state mouse models of ...[more]
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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.
This model is hosted on BioModels Database
and identified
by: BIOMD0000000505
.
To cite BioModels Database, please use: BioModels Database: An enhanced, curated and annotated resource
for published quantitative kinetic models
.
To the extent possible under law, all copyright and related or
neighbouring rights to this encoded model have been dedicated to the public
domain worldwide. Please refer to CC0 Public Domain
Dedication
for more information.
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This model is described in the article:
Biochemical competition makes fatty-acid β-oxidation vulnerable to substrate overload.
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This model is hosted on BioModels Database
and identified
by: BIOMD0000000506
.
To cite BioModels Database, please use: BioModels Database: An enhanced, curated and annotated resource
for published quantitative kinetic models
.
To the extent possible under law, all copyright and related or
neighbouring rights to this encoded model have been dedicated to the public
domain worldwide. Please refer to CC0 Public Domain
Dedication
for more information.
2024-09-02 | BIOMD0000000506 | BioModels
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2013-12-10 | E-GEOD-39752 | biostudies-arrayexpress
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2020-07-06 | PXD017678 | Pride
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