Drp1 Controls Complex II assembly and Fatty Acid Oxidation by Sdhaf2 Action on Mitochondria
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ABSTRACT:
PROVIDER: PRJNA1041739 | ENA |
REPOSITORIES: ENA
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Project description:The Dynamin-related GTPase, Drp1 (encoded by Dnm1l) plays a central role in mitochondrial fission and is requisite for numerous cellular processes however its role in oxidative metabolism remains unclear. Herein, we show that among human tissues, skeletal muscle exhibits the strongest correlations with the DNM1L gene. Knockdown of Drp1 (Drp1-KD) promoted mitochondrial hyperfusion in the muscle of male mice. Reduced fatty acid oxidation and accumulation of intramyocellular lipids along with increased muscle succinate was observed in Drp1-KD muscle. Muscle Drp1-KD reduced Complex II assembly and activity as a consequence of diminished mitochondrial translocation of succinate dehydrogenase assembly factor 2 (Sdhaf2). Restoration of Sdhaf2, normalized Complex II activity and lipid oxidation in Drp1-KD myocytes. Drp1 appears critical in maintaining mitochondrial Complex II assembly and fatty acid oxidation, suggesting a mechanistic link between mitochondrial morphology and skeletal muscle lipid metabolism which is of clinical significance in combatting metabolic diseases.
2024-01-26 | GSE248081 | GEO
Project description:Mitochondria undergo continuous cycles of fission and fusion to promote inheritance, regulate quality control, and mitigate organelle stress. More recently, this process of mitochondrial dynamics has been demonstrated to be highly sensitive to nutrient supply, ultimately conferring bioenergetic plasticity to the organelle. However, whether regulators of mitochondrial dynamics play a causative role in nutrient regulation remains unclear. In this study, we generated a cellular loss-of-function model for dynamin-related protein 1 (DRP1), the primary regulator of outer membrane mitochondrial fission. Loss of DRP1 (shDRP1) resulted in extensive ultrastructural and functional remodeling of mitochondria, characterized by pleomorphic enlargement, increased electron density of the matrix, and defective NADH and succinate oxidation. Despite increased mitochondrial size and volume, shDRP1 cells exhibited reduced cellular glucose uptake and mitochondrial fatty acid oxidation. Untargeted transcriptomic profiling revealed severe downregulation of genes required for cellular and mitochondrial calcium homeostasis, inhibition of ATP-stimulated calcium flux, and impaired substrate oxidation stimulated by calcium levels. The insights obtained herein suggest that DRP1 regulates fatty acid oxidation by altering whole-cell and mitochondrial calcium dynamics. These findings are relevant to the targetability of mitochondrial fission and have clinical relevance in the identification of treatments for fission-related pathologies such as hereditary neuropathies, inborn errors in metabolism, cancer, and chronic diseases.
2021-09-13 | GSE162983 | GEO
Project description:We performed RNAseq analysis of 3 days in vitro activated control and Drp1 KO T cells to investigate the role of Drp1 in regulating global transcriptional changes upon activation in T cells. Our analysis shows that Drp1 sustains metabolic reprogramming upon TCR stimulation. Indeed, in Drp1 KO T cells most of the genes encoding for glycolytic enzymes are down-regulated, while TCA cycle and oxidative phosphorylation genes, as well as several genes encoding enzymes of fatty acid synthesis and beta-oxidation, are upregulated.
2018-12-11 | GSE112143 | GEO
Project description:Loss of fatty acid oxidation in mitochondria promotes epigenetic control of cardiomyocyte maturation status
| PRJNA723273 | ENA
Project description:Cellular senescence is a stress-induced irreversible cell cycle arrest involved in tumor suppression and aging. Many stresses, such as telomere shortening and oncogene activation, induce senescence by damaging nuclear DNA. However, the mechanisms linking DNA damage to senescence remain unclear. Here, we show that DNA damage response (DDR) signaling to mitochondria triggers senescence. A genome-wide siRNA screen implicated the outer mitochondrial transmembrane protein BNIP3 in senescence induction. We found that BNIP3 is a substrate of the DDR kinase ATM and contributes to an increase in the number of mitochondrial cristae upon DNA damage. Stable isotope labeling metabolomics indicated that this increase in cristae enhances the oxidation of fatty acids to acetyl-CoA. Notably, pharmacological activation of fatty acid oxidation alone induced senescence both in vitro and in vivo. Our findings suggest that mitochondrial energy metabolism plays a critical role in senescence induction and is a potential intervention target to control senescence.
2024-10-30 | GSE272659 | GEO
Project description:vanEunen2013 - Network dynamics of fatty acid β-oxidation (time-course model)
Lipid metabolism plays an important role in the development of metabolic syndrome, a major risk factor for cardiovascular disease and diabetes. This model gives insights into the response of lipid oxidation to dietart and medical interventions. The model predicts the rate of lipid oxidation and the time course of most acyl carnitines. There are two models described in the paper, (i) steady-state model [ BIOMD0000000505
], (ii) time-course model [ BIOMD0000000506
]. This model corresponds to the time-course model.
This model is described in the article:
Biochemical competition makes fatty-acid β-oxidation vulnerable to substrate overload.
van Eunen K, Simons SM, Gerding A, Bleeker A, den Besten G, Touw CM, Houten SM, Groen BK, Krab K, Reijngoud DJ, Bakker BM.
PLoS Comput Biol. 2013;9(8):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.
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
Project description:vanEunen2013 - Network dynamics of fatty acid β-oxidation (steady-state model)
Lipid metabolism plays an important role in the development of metabolic syndrome, a major risk factor for cardiovascular disease and diabetes. This model gives insights into the response of lipid oxidation to dietart and medical interventions. The model predicts the rate of lipid oxidation and the time course of most acyl carnitines. There are two models described in the paper, (i) steady-state model [ BIOMD0000000505
], (ii) time-course model [ BIOMD0000000506
]. This model corresponds to the steady-state model.
This model is described in the article:
Biochemical competition makes fatty-acid β-oxidation vulnerable to substrate overload.
van Eunen K, Simons SM, Gerding A, Bleeker A, den Besten G, Touw CM, Houten SM, Groen BK, Krab K, Reijngoud DJ, Bakker BM.
PLoS Comput Biol. 2013;9(8):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.
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.
2024-09-02 | BIOMD0000000505 | BioModels
Project description:Mitochondrial trifunctional protein deficiency, due to mutations in hydratase subunit A (HADHA), results in sudden infant death syndrome with no cure. To reveal the disease etiology, we generated stem cell-derived cardiomyocytes from HADHA-deficient hiPSCs and accelerated their maturation via an engineered microRNA maturation cocktail that upregulated the epigenetic regulator, HOPX. Here we report, matured HADHA mutant cardiomyocytes treated with an endogenous mixture of fatty acids manifest the disease phenotype: defective calcium dynamics and repolarization kinetics which results in a pro-arrhythmic state. Single cell RNA-seq reveals a cardiomyocyte developmental intermediate, based on metabolic gene expression. This intermediate gives rise to mature-like cardiomyocytes in control cells but, mutant cells transition to a pathological state with reduced fatty acid beta-oxidation, reduced mitochondrial proton gradient, disrupted cristae structure and defective cardiolipin remodeling. This study reveals that HADHA (tri-functional protein alpha), a monolysocardiolipin acyltransferase-like enzyme, is required for fatty acid beta-oxidation and cardiolipin remodeling, essential for functional mitochondria in human cardiomyocytes.
2019-08-25 | GSE135595 | GEO
Project description:Repair of airway epithelia requires metabolic rewiring towards fatty acid oxidation
2023-01-31 | GSE218663 | GEO
Project description:Metabolic remodeling is one of the earliest events that occur during the early differentiation of embryonic stem cells (ESCs), but how these metabolic changes are regulated and participate in the cell differentiation is still largely undissected. Here, we define the fatty acid metabolism as a key player in definitive endoderm (DE) differentiation from human ESCs. During DE differentiation, lipogenesis is decreased while fatty acid β oxidation is enhanced. This dynamic is due to the phosphorylation of lipogenic enzyme acetyl-CoA carboxylase (ACC), which is mediated by AMP-activated protein kinase (AMPK) and inhibits the de novo fatty acid synthesis. More importantly, inhibition of fatty acid synthesis by either its inhibitors or AMPK agonist, significantly promotes the human endoderm differentiation, while blockade of the fatty acid oxidation by genetic manipulation or chemical antagonists impairs the differentiation. The de novo fatty acid synthesis inhibition and fatty acid β oxidation maintaining contribute to the accumulation of cellular acetyl-CoA, which is the essential substrate for protein acetylation. Further study reveals that SMAD3 acetylation and the subsequent subcellular localization exhibit significant change upon interfering fatty acid metabolism. Mechanistically, the accumulation of cellular acetyl-CoA guarantees the acetylation of key transcription factor SMAD3, which further causes the nuclear localization and activation of SMAD signaling pathway to promote DE differentiation. Thus, our current study reveals a fatty acid synthesis/oxidation shift during early differentiation and presents an instructive role of fatty acid metabolism in regulating human early endoderm differentiation.
2023-07-02 | GSE218319 | GEO