GNPS - Cocaine perturbs mitovesicle biology in the brain
Ontology highlight
ABSTRACT:
INSTRUMENT(S): Q Exactive HF
ORGANISM(S): Mus Musculus (ncbitaxon:10090)
SUBMITTER: 
Dr. Thomas A. Neubert
PROVIDER: MSV000089323 | GNPS | Wed Apr 27 15:29:00 BST 2022
REPOSITORIES: GNPS
Similar Datasets
Project description:Cocaine is one of the most abused psychostimulants in the United States. In addition to its established roles in the regulation of dopaminergic circuitries, cocaine has a broader mechanism of action, including global alterations in brain metabolism and mitochondrial homeostasis. Our group recently identified a subpopulation of non-microvesicular, non-exosomal extracellular vesicles of mitochondrial origin, mitovesicles (mtVs), and provided a method to isolate mtVs from brain parenchyma. Given their origin, we hypothesized that mtVs could be affected by mitochondrial abnormalities induced by chronic cocaine exposure. Therefore, we analyzed mtVs from hemibrains of 3-month-old mice that received for two weeks intraperitoneal injections of cocaine or saline as control. MtVs from the brain extracellular space of cocaine-intoxicated mice were enlarged and more numerous when compared to controls. Moreover, cocaine stimulated higher intracellular mitochondrial fission and higher levels of upstream (but not downstream) mitophagy pathways, suggesting increased mitochondrial fragmentation and a block in mitophagy flux. Lastly, cocaine impaired brain mtV cargo loading as revealed by Mass Spec analysis, causing an alteration in mtV ATP production capacity. These data suggest that mtVs are a previously unidentified player in the biology of cocaine addiction and that target therapies to fine tune brain mtV functionality may be beneficial to mitigate chronic cocaine pathology.
2022-04-27 | MSV000089323 | MassIVE
Project description:Qosa2014 - Mechanistic modeling that
describes Aβ clearance across BBB
Qosa2014 - Mechanistic modeling that
describes Aβ clearance across BBB.
Encoded non-curated model. Issues:
- Confusing equation 6
- Missing initial values for spices
This model is described in the article:
Differences in amyloid-?
clearance across mouse and human blood-brain barrier models:
kinetic analysis and mechanistic modeling.
Qosa H, Abuasal BS, Romero IA,
Weksler B, Couraud PO, Keller JN, Kaddoumi A.
Neuropharmacology 2014 Apr; 79:
668-678
Abstract:
Alzheimer's disease (AD) has a characteristic hallmark of
amyloid-? (A?) accumulation in the brain. This accumulation of
A? has been related to its faulty cerebral clearance. Indeed,
preclinical studies that used mice to investigate A? clearance
showed that efflux across blood-brain barrier (BBB) and brain
degradation mediate efficient A? clearance. However, the
contribution of each process to A? clearance remains unclear.
Moreover, it is still uncertain how species differences between
mouse and human could affect A? clearance. Here, a modified
form of the brain efflux index method was used to estimate the
contribution of BBB and brain degradation to A? clearance from
the brain of wild type mice. We estimated that 62% of
intracerebrally injected (125)I-A?40 is cleared across BBB
while 38% is cleared by brain degradation. Furthermore,
in vitro and in silico studies were performed to compare
A? clearance between mouse and human BBB models. Kinetic
studies for A?40 disposition in bEnd3 and hCMEC/D3 cells,
representative in vitro mouse and human BBB models,
respectively, demonstrated 30-fold higher rate of (125)I-A?40
uptake and 15-fold higher rate of degradation by bEnd3 compared
to hCMEC/D3 cells. Expression studies showed both cells to
express different levels of P-glycoprotein and RAGE, while LRP1
levels were comparable. Finally, we established a mechanistic
model, which could successfully predict cellular levels of
(125)I-A?40 and the rate of each process. Established
mechanistic model suggested significantly higher rates of A?
uptake and degradation in bEnd3 cells as rationale for the
observed differences in (125)I-A?40 disposition between mouse
and human BBB models. In conclusion, current study demonstrates
the important role of BBB in the clearance of A? from the
brain. Moreover, it provides insight into the differences
between mouse and human BBB with regards to A? clearance and
offer, for the first time, a mathematical model that describes
A? clearance across BBB.
This model is hosted on
BioModels Database
and identified by:
MODEL1409240002.
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.
2015-04-15 | MODEL1409240002 | BioModels
Project description:Mitochondrial dysfunction was highlighted as a crucial vulnerability factor for the development of depression. However, systemic studies assessing stress-induced changes in mitochondria-associated genes in brain regions relevant to depression symptomatology remain scarce. Here, we performed a genome-wide transcriptomic study to examine mitochondrial gene expression in the prefrontal cortex (PFC) and nucleus accumbens (NAc) of mice exposed to multimodal chronic restraint stress. We identified mitochondria-associated gene pathways as most prominently affected in the PFC and with lesser significance in the NAc. A more detailed mitochondrial gene expression analysis revealed that in particular mitochondrial DNA-encoded subunits of the oxidative phosphorylation complexes were altered in the PFC. The comparison of our data with a reanalyzed transcriptome data set of chronic variable stress mice and major depression disorder subjects showed that the changes in mitochondrial DNA-encoded genes are a feature generalizing to other chronic stress-protocols as well and might have translational relevance. Finally, we provide evidence for changes in mitochondrial outputs in the PFC following chronic stress that are indicative of mitochondrial dysfunction. Collectively, our work reinforces the idea that changes in mitochondrial gene expression are key players in the prefrontal adaptations observed in individuals with high behavioral susceptibility and resilience to chronic stress.
2020-09-20 | GSE148629 | GEO
Project description:Gene expression profiling reveals age dependent functional alternation in SAMP8 mice brain. We evaluated the effects of aging on SAMP8 mice brain. We performed an untargeted whole-genome transcriptome analysis to explore functionality age dependent changes of brain in SAMP8 mice.
2023-10-04 | GSE236414 | GEO
Project description:Stressors challenge metabolic processes to adapt to ever-changing environmental conditions and herein, the brain is exceptionally amenable to change. Simultaneously, the high cerebral energy demands may render the brain particularly vulnerable to the metabolic consequences of psychological stress. Mitochondria are central organelles within energy metabolism, known to dynamically adjust function according to shifts in metabolic demands, and thus pivotal in the stress response. It is largely unclear how mitochondria respond to a psychological stressor and how mitochondria orchestrate their actions with other organelles, such as the endoplasmatic reticulum (ER). To address these questions we subjected male mice to chronic social defeat stress (CSD) and analyzed different subcellular brain fractions using label-free proteomics: mitochondrial associated membranes (MAMs), ER, and crude and pure mitochondrial fractions. Although insufficient to warrant a protein pathway analysis, we identified a few noteworthy differentially regulated proteins. These included decreased levels of SH3GL2 (SH3 Domain Containing GRB2 Like 2 or Endophilin 1) in the crude mitochondrial fraction of stressed mice, which may be related to impaired presynaptic calcium influx. In line, CACNA1A (Calcium Voltage-Gated Channel Subunit Alpha1 A) was absent in the pure mitochondrial fraction from CSD-exposed mice, a finding also suggestive of an impaired mitochondrial calcium flux. Then, in the MAM-fraction we observed an absence of HK3 (hexokinase 3) in CSD-treated mice, which may be linked to the CSD-induced cerebral hyperglycemia reported previously. Although verification is still required, our findings revealed a number of differentially expressed proteins possibly critical in the metabolic response to chronic stress.
2022-10-13 | PXD015983 | Pride
Project description:Increasing energy expenditure through activation of brown adipose tissue (BAT) thermogenesis is an attractive approach to counteract obesity. Thus, it is essential to understand molecular mechanisms that control BAT functions. Here, we describe signal transducer and activator of transcription (STAT) 5 as key regulator of BAT functionality. We found that STAT5 is necessary for acute cold-induced temperature maintenance and stimulated lipid breakdown in BAT using mice that harbour an adipocyte-specific deletion of Stat5a/b genes. In addition, the mitochondrial respiratory capacity of primary differentiated brown adipocytes from STAT5 deficient mice was diminished. We show that increased sensitivity to cold stress upon STAT5 deficiency was associated with reduced expression of thermogenic key player uncoupling protein 1, while decreased stimulated lipolysis of STAT5-deficient BAT explants was linked to decreased protein kinase A activity. In addition, brown remodeling of white fat was diminished following chronic β-adrenergic stimulation. This impairment was linked to a decrease in mitochondrial functionality. We conclude that STAT5 is essential for the β-adrenergic responsiveness of brown adipose tissue and the physiologic function of thermogenic adipose tissue.
2020-05-28 | GSE137678 | GEO
Project description:Although mitochondrial dysfunctions are implicated in the pathogenesis of obesity, the molecular mechanisms underlying obesity-related metabolic abnormalities are still not well established. To acquire a comprehensive picture of mitochondrial molecular changes within metabolically active tissues, we focused on hepatic and muscle whole cellular transcriptome and mitochondrial proteome alterations in 16 and 48 weeks old high fat diet (HFD)-feed wild type C57BL/6J and hyperphagic, genetically modified mice with leptin dysfunction (ob/ob and db/db). On transcriptome level, the most discriminative hepatic alterations distinguished between genetically modified and wild type mice, and between overnight fasted and non-fasted mice, while the muscle transcriptional alterations related mainly to the fasting state. The fractions of uniquely different proteins were consistently higher in hyperphagic than in HFD-fed mice and in fasted than non-fasted mice . The liver samples revealed overall higher number of differentially expressed RNAs and proteins than muscle samples. Differentially expressed genes and proteins in the liver, but not in the muscle, could be assigned to several Gene Ontology terms, including oxidation-reduction and several metabolic processes. Thus, altered expression of genes and proteins accompanied the state of obesity and was quantitatively different in the liver and muscle. Our parallel microarray- and quantitative mitochondrial mass spectrometry-based study performed on hepatic and muscle samples identified a higher number of differentially expressed proteins than any other studies investigating obesity-related proteomes. However, even with our integrated transcriptomic and proteomic approach still many details and dynamics of a chain of metabolic events leading to obesity-related mitochondrial dysfunctions remain unresolved . 48 samples each of liver and muscle (total samples: 96). Samples splitted equally according to 3 criterions: age (24 young/24 old), fasting status (24 fasted/24 non fasted), and strain+diet (12 each: B6.V-Lep ob/J+D12450B, B6.BKS(D)-Lep rdb/J+D12450B, C57BL/6J+D12450B, C57BL/6J+D12492). Overall 3 replicates for each strain+diet/age/fasting_status combination. Low fat diet = D12450B; high fat diet = D12492.
2013-05-01 | E-GEOD-43691 | biostudies-arrayexpress
Project description:Proving functionality in the host environment is a crucial step in antimicrobial development pipelines. Antibiotics targeting fatty acid synthesis (FASII) of the major pathogen Staphylococcus aureus actively inhibit FASII but do not prevent in vivo growth, as bacteria compensate the FASII block by using environmental fatty acids. We used proteomics and phosphoproteomics to elucidate S. aureus responses to anti-FASII in host-relevant conditions. S. aureus responded to anti-FASII treatment in serum by massive reprogramming, including overall increases in stress response proteins, and decreases in virulence factors. Adaptation is accelerated by pretreatment with hydrogen peroxide. These findings suggested that anti-FASII adapted cells might be better prepared for survival and less equipped to damage the host. Infection by anti-FASII-adapted versus non-treated S. aureus was challenged in the Galleria mellonella model. Time to mortality was longer in insects infected by anti-FASII-treated bacteria compared to those infected by non-treated S. aureus. However, bacterial counts in infected dead insects were comparable for both groups. These results support the hypothesis that higher stress response and lower virulence factor expression, as shown here in FASII-antibiotic-adapted bacteria, may prepare S. aureus for chronic infection.
2022-07-01 | MSV000089781 | MassIVE
Project description:Here, we present a novel approach to interrogate the mitochondrial DNA (mtDNA) methylome at single base resolution using targeted bisulfite sequencing. We applied this method to investigate mitochondrial DNA methylation patterns in post-mortem superior temporal gyrus and cerebellum brain tissue from seven human donors. We show that mitochondrial DNA methylation patterns are relatively low but conserved, with peaks in DNA methylation >5% at a number of sites and higher levels of methylation at non-CpG compared to CpG sites. We identify a number of loci that show differential DNA methylation patterns associated with age, sex and brain region. Finally we validate differences between cortical and cerebellar mitochondrial DNA methylation patterns using data previously generated using methylated DNA immunoprecipitation sequencing.
2022-12-20 | GSE189565 | GEO
Project description:Best2009 - Homeostatic mechanisms in dopamine
synthesis and release
Encoded non-curated model. Issues:
- Initial concentrations for hva, tyrpool, NADPH and NADP
are missing
- Reaction VMAT requires two substrates to match the formula
proposed in the article
This model is described in the article:
Homeostatic mechanisms in
dopamine synthesis and release: a mathematical model.
Best JA, Nijhout HF, Reed MC.
Theor Biol Med Model 2009; 6: 21
Abstract:
BACKGROUND: Dopamine is a catecholamine that is used as a
neurotransmitter both in the periphery and in the central
nervous system. Dysfunction in various dopaminergic systems is
known to be associated with various disorders, including
schizophrenia, Parkinson's disease, and Tourette's syndrome.
Furthermore, microdialysis studies have shown that addictive
drugs increase extracellular dopamine and brain imaging has
shown a correlation between euphoria and
psycho-stimulant-induced increases in extracellular dopamine 1.
These consequences of dopamine dysfunction indicate the
importance of maintaining dopamine functionality through
homeostatic mechanisms that have been attributed to the
delicate balance between synthesis, storage, release,
metabolism, and reuptake. METHODS: We construct a mathematical
model of dopamine synthesis, release, and reuptake and use it
to study homeostasis in single dopaminergic neuron terminals.
We investigate the substrate inhibition of tyrosine hydroxylase
by tyrosine, the consequences of the rapid uptake of
extracellular dopamine by the dopamine transporters, and the
effects of the autoreceoptors on dopaminergic function. The
main focus is to understand the regulation and control of
synthesis and release and to explicate and interpret
experimental findings. RESULTS: We show that the substrate
inhibition of tyrosine hydroxylase by tyrosine stabilizes
cytosolic and vesicular dopamine against changes in tyrosine
availability due to meals. We find that the autoreceptors
dampen the fluctuations in extracellular dopamine caused by
changes in tyrosine hydroxylase expression and changes in the
rate of firing. We show that short bursts of action potentials
create significant dopamine signals against the background of
tonic firing. We explain the observed time courses of
extracellular dopamine responses to stimulation in wild type
mice and mice that have genetically altered dopamine
transporter densities and the observed half-lives of
extracellular dopamine under various treatment protocols.
CONCLUSION: Dopaminergic systems must respond robustly to
important biological signals such as bursts, while at the same
time maintaining homeostasis in the face of normal biological
fluctuations in inputs, expression levels, and firing rates.
This is accomplished through the cooperative effect of many
different homeostatic mechanisms including special properties
of tyrosine hydroxylase, the dopamine transporters, and the
dopamine autoreceptors.
This model is hosted on
BioModels Database
and identified by:
MODEL1502230000.
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.
2015-04-15 | MODEL1502230000 | BioModels