Distinctive metabolic remodeling in TYMP deficiency beyond mitochondrial dysfunction
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA924032 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR23085385.fastq.gz | Fastqsanger.gz | |||
| SRR23085386.fastq.gz | Fastqsanger.gz | |||
| SRR23085387.fastq.gz | Fastqsanger.gz | |||
| SRR23085388.fastq.gz | Fastqsanger.gz | |||
| SRR23085389.fastq.gz | Fastqsanger.gz |
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Project description:Purpose: Mitochondrial neurogastrointestinal encephalomyopathy (MNGIE), a rare mitochondrial encephalomyopathy subtype, is caused by mutations of thymidine phosphorylase (TYMP). As a metabolic enzyme localized in the cytoplasm, the biological processes disturbed by TYMP functional defect are supposed to be not limited in the abnormal replication of mitochondrial DNA. This study aimed to elucidate the characteristic biological alterations and associated homeostatic regulation caused by TYMP deficiency. Methods: Clinical evaluation and genetic analysis were performed on three patients from two independent families carrying heterozygous TYMP variants. Molecular dynamic (MD) simulation and nucleosides detection were used to investigate the pathogenicity of the variants. Plasma from patients with MNGIE and m.A3243G MELAS and healthy volunteers were analyzed by targeted and untargeted metabolomics to characterize the metabolic profiles of MNGIE. Transcriptomics analysis and bioenergetic studies were performed on skin fibroblasts from these three groups of subjects. Results: Three novel TYMP pathogenic variants were identified in our MNGIE patients. Total 72 plasma metabolites were identified as specific alterations of MNGIE patients through comparing the differentially changed metabolites in MNGIE patients and m.A3243G MELAS patients. Beside pyrimidine metabolism, MNGIE patients showed significant changes in multiple metabolisms, such as bile acids metabolism, caffeine metabolism and steroid hormone metabolism. Despite comparable mitochondrial dysfunction existing in fibroblasts from patients with TYMP deficiency and ones with m.A3243G mutation, a distinct downregulated cholesterol metabolism and fatty acids (FAs) metabolism were revealed in the fibroblasts from MNGIE patients via multiple analysis of metabolites levels, metabolic enzymes expression, mitochondrial substrates dependency and transcription factors expression. Conclusions: Our findings revealed a more expansive metabolic disturbance may be caused by TYMP deficiency beyond mitochondrial disfunction, extending a comprehensive understanding of the biochemical outcome of TYMP deficiency.
2025-03-01 | GSE222921 | GEO
Project description:Hypertrophic cardiomyopathy (HCM) is one of the most frequent inherited heart condition and a well-established risk factor for cardiovascular mortality worldwide. Although hypertrophy is traditionally regarded as an adaptive response to increased workload caused by physiological or pathological stress, prolonged hypertrophy can lead to heart failure characterized by impaired systolic function, increased apoptosis, fibrosis, ventricular dilation, and impaired metabolic substrate flexibility. While the key regulators for cardiac hypertrophy are well studied, the role of Prdm16 in this process remains poorly understood. In the present study, we demonstrate that Prdm16 is dispensable for cardiac development. However, it is required in the adult heart to preserve mitochondrial function and inhibit hypertrophy with advanced age. Cardiac-specific deletion of Prdm16 results in cardiac hypertrophy, excessive ventricular fibrosis, mitochondrial dysfunction, and impaired metabolic flexibility, leading to heart failure. We demonstrate that Prdm16 and euchromatic histone-lysine N- methyltransferase factors (Ehmts) act together to reduce the expression of fetal genes reactivated in pathological hypertrophy by inhibiting the functions of pro- hypertrophic transcription factor Myc. Although young Prdm16 knockout mice show normal cardiac function, they are predisposed to develop heart failure in response to metabolic stress. Collectively, our results demonstrate that Prdm16 protects the heart against age-dependent cardiac hypertrophy, fibrosis, mitochondrial dysfunction, adverse metabolic remodeling, and heart failure.
2020-09-21 | GSE153988 | GEO
Project description:Prdm16 deficiency leads to age-dependent cardiac hypertrophy, adverse remodeling, mitochondrial dysfunction, and heart failure
| PRJNA644651 | ENA
Project description:Mitochondrial DNA (mtDNA) encodes essential components of the respiratory chain and loss of mtDNA leads to mitochondrial dysfunction and neurodegeneration. Mitochondrial transcription factor A (TFAM) is an essential component of mtDNA replication and a regulator of mitochondrial copy number in cells. Studies have shown that TFAM knockdown leads to mitochondrial dysfunction and respiratory chain deficiencies. Using gene expression analysis, we aimed to investigate the effects of mtDNA dysfunction in the CNS at the molecular level. We used microarray analysis to investigate gene expression in cases of mitochondrial dysfunction in the CNS. RNA was purified from the late third instar larval CNS from control larvae, or larvae over-expressing mitochondrial transcription factor A (TFAM) in post-mitotic neurons using the neuron specific driver nsyb-Gal4. Three replicates are included for each condition.
2013-12-20 | E-GEOD-53509 | biostudies-arrayexpress
Project description:We characterized the global response of plants carrying a mitochondrial dysfunction induced by the expression of the unedited form of the ATP synthase 9 subunit. The u-ATP9 transgene driven by A9 and Apetala3 promoters induce mitochondrial dysfunction revealed by a decrease in both oxygen uptake and ATP levels, with an increase in ROS and a concomitant oxidative stress response. The transcriptome analysis of young Arabidopsis flowers, validated by RT-PCR and enzymatic or functional tests, show dramatic changes in u-ATP9 plants. Both lines present a modification in the expression of several genes involved in carbon, lipid and cell wall metabolism, suggesting that an important metabolic readjustment occurs in plants with a mitochondrial dysfunction. Interestingly, transcript levels involved in mitochondrial biogenesis, protein synthesis, and degradation are affected. Moreover, several mRNA levels for transcription factors and DNA binding proteins were also changed. Some of them are involved in stress and hormone response, suggesting that several signaling pathways overlap. Indeed, the transcriptome data reveal that the mitochondrial dysfunction dramatically alters genes involved in signaling pathways, including those involved in ethylene, absicic acid and auxin signal transduction. Our data suggest that the mitochondrial dysfunction model used in this rapport may be useful to uncover the retrograde signaling mechanism between the nucleus and mitochondria in plant cells. Arabidopsis oligonucleotide microarrays fabricated by the University of Arizona contain 26,000 oligonucleotides (http://www.ag.arizona.edu/microarray/). RNA was isolated from 6-week-old flowers from u-ATP9 and wt plants. The experimental (mutant) and reference (wild type) RNA samples were reverse-transcribed and directly labeled with either Cy5-dUTP or Cy3-dUTP fluorescent dye (GE Healthcare), using random hexamer primers (Invitrogen). Excess nucleotides and primers were removed using QIAquick PCR Purification Kit (Qiagen). Labeled samples were mixed and then hybridized to microarray for 15 h at 60°C. The slides were washed at room temperature in three wash steps: 2 x SSC, 0.5% SDS; 0.5 x SSC; and 0.05 x SSC for 5 min each with gentle shaking. The slides were scanned with a GenePix 4000B Scanner (Axon Instruments Inc., Union City, CA). Normalization between the Cy3 and Cy5 fluorescent dye emission channels was achieved by adjusting the levels of both image intensities. The experiments were repeated four times with samples from different experiments, as biological replicates. In dye swapping experiments, the RNA samples from different experiments were reciprocally labeled, both as a biological and technical repetition for comparing the reproducibility of the experiments. Hybridization intensities for each microarray element were measured using ScanAlyze 4.24 (available at http://genome-www4.stanford.edu/MicroArray/SMD/restech.html). The two channels were normalized in log space using the z-score normalization on a 95% trimmed data set. We removed unreliable spots according to the following criteria: spots flagged as having false intensity caused by dust or background on the array were removed; and spots for which intensity was less than three fold above background were also eliminated. Data from multiple experiments were normalized (Bolstad, 2003) and signals from spots from different experiments were statistically analyzed using Significance Analysis of Microarrays using the one class response (SAM, http://www-stat.stanford.edu/~tibs/SAM/), cut at a false discovery rate < 10% (Tusher, 2001).
2009-02-15 | E-GEOD-14240 | biostudies-arrayexpress
Project description:Distinctive roles for the chromatin remodeling ATPases Brg1 and Brm in early zebrafish embryos
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Project description:Differential gene expression in mouse models of mitochondrial dysfunction
2017-11-14 | GSE96518 | GEO
Project description:DallePazze2014 - Cellular senescene-induced
mitochondrial dysfunction
This model is described in the article:
Dynamic modelling of
pathways to cellular senescence reveals strategies for targeted
interventions.
Dalle Pezze P, Nelson G, Otten EG,
Korolchuk VI, Kirkwood TB, von Zglinicki T, Shanley DP.
PLoS Comput. Biol. 2014 Aug; 10(8):
e1003728
Abstract:
Cellular senescence, a state of irreversible cell cycle
arrest, is thought to help protect an organism from cancer, yet
also contributes to ageing. The changes which occur in
senescence are controlled by networks of multiple signalling
and feedback pathways at the cellular level, and the interplay
between these is difficult to predict and understand. To
unravel the intrinsic challenges of understanding such a highly
networked system, we have taken a systems biology approach to
cellular senescence. We report a detailed analysis of
senescence signalling via DNA damage, insulin-TOR, FoxO3a
transcription factors, oxidative stress response, mitochondrial
regulation and mitophagy. We show in silico and in vitro that
inhibition of reactive oxygen species can prevent loss of
mitochondrial membrane potential, whilst inhibition of mTOR
shows a partial rescue of mitochondrial mass changes during
establishment of senescence. Dual inhibition of ROS and mTOR in
vitro confirmed computational model predictions that it was
possible to further reduce senescence-induced mitochondrial
dysfunction and DNA double-strand breaks. However, these
interventions were unable to abrogate the senescence-induced
mitochondrial dysfunction completely, and we identified
decreased mitochondrial fission as the potential driving force
for increased mitochondrial mass via prevention of mitophagy.
Dynamic sensitivity analysis of the model showed the network
stabilised at a new late state of cellular senescence. This was
characterised by poor network sensitivity, high signalling
noise, low cellular energy, high inflammation and permanent
cell cycle arrest suggesting an unsatisfactory outcome for
treatments aiming to delay or reverse cellular senescence at
late time points. Combinatorial targeted interventions are
therefore possible for intervening in the cellular pathway to
senescence, but in the cases identified here, are only capable
of delaying senescence onset.
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BIOMD0000000582.
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2024-09-02 | BIOMD0000000582 | BioModels
Project description:The mitochondrial network forms a central hub in cellular metabolism, adapting to a vast array of environmental and cellular signals to maintain cellular homeostasis. Derangements to this network can lead to mitochondrial diseases but are also increasingly recognised to be a contributing factor in common disorders including heart failure, neurodegeneration, cancer, or the natural ageing process. Despite its central importance, little is known how the cell responds to a mitochondrial dysfunction, contributing to our lack of affective treatment strategies. Here we performed an unbiased genetic deficiency screen in the fruit fly to identify mechanisms that can rescue a lethal mitochondrial dysfunction. After screening ~40% of the fly genome, we identified 10 genes from four distinct cellular pathways that rescued the mitochondrial dysfunction upon heterozygous deletion, resulting in viable adult flies. The data presented here includes proteomic analysis of larvae of control, mutant, and rescued lines.
2024-12-01 | PXD041418 | Pride
Project description:Distinctive roles for the chromatin remodeling ATPases Brg1 and Brm in early zebrafish embryos [ChIP-seq]
| PRJNA732404 | ENA