Transcriptome analysis upon C6orf203 silencing
Ontology highlight
ABSTRACT:
ORGANISM(S): Homo sapiens
PROVIDER: GSE123683 | GEO | 2019/06/13
REPOSITORIES: GEO
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Project description:The aim of this project was to search for the new factors engaged in mitochondrial nucleic acids metabolism under stress conditions. To this end we treated human 293 cells with mitochondrial replication/transcription inhibitor ethidium bromide and we compared proteomes of untreated vs treated cells. We were looking for the proteins whose level would be differentially regulated in response to disturbed mitochondrial gene expression. In our studies we utilized a stable 293 cell line that inducible expresses a fusion of EGFP with mitochondria targeting sequence. This approach enabled us to control mitochondrial import by analysis of the abundance of mitochondrial EGFP marker. We isolated highly purified mitochondria from the cells, lysed them and subjected protein extracts to labelling with iTRAQ reagents. We performed quantitative analysis of stress- induced changes of human mitochondrial proteome with the use of MaxQuant software.
2019-06-13 | PXD012055 | Pride
Project description:Stress response pathways detect and alleviate many adverse conditions to safeguard cell and tissue homeostasis, yet their prolonged activation induces apoptosis and disrupts organismal health. How stress responses are turned off at the right time and place remains poorly understood. Here, we report a ubiquitin-dependent mechanism to silence the cellular response to mitochondrial protein import stress. Critical to this process is the silencing factor of the integrated stress response (SIFI), a large E3 ligase complex mutated in ataxia that degrades both unimported mitochondrial precursors and stress response components. By recognizing bifunctional substrate motifs that equally encode protein localization and stability, the SIFI complex can rapidly turn off a general stress response after a specific stress has been resolved. Pharmacological stress response silencing sustains cell survival even if stress resolution failed, which underscores the importance of signal termination and provides a roadmap for treating neurodegenerative diseases caused bymitochondrial import defects.
2023-11-22 | GSE232191 | GEO
Project description:ER stress underlies numerous severe pathologies. We have metabolically perturbed normal fibroblasts in order to study the biological roles of microRNAs (miRs) under mild and extended ER stress. We now report that miR-4488 quenches inflammation-associated gene expression in such metabolically perturbed cells. Furthermore, we define miR-4488 as a non-canonical miRNA derived from the expansion segment ES7L of the 28S ribosomal RNA. Generation of miR-4488 requires Dicer, but not Drosha. Moreover, its generation involves the autophagy-lysosome route and is inhibited when this pathway is blocked, thus unveiling an anti-inflammatory role for lysosomes engaged at the onset of stress. Mechanistically, miR-4488 suppresses the expression of NFKB2 and RELB, whose mRNAs specifically associate with miR-4488 exclusively upon stress. This selectivity suggests that miR-4488 may have promise for treating mild ER stress-associated diseases.
2026-04-09 | GSE244149 | GEO
Project description:Background: Mitochondria carry out essential functions in eukaryotic cells. The mitochondrial genome encodes factors critical to support oxidative phosphorylation and mitochondrial protein import necessary for these functions. However, organisms like budding yeast can readily lose their mitochondrial genome, yielding respiration-deficient petite mutants. The fission yeast Schizosaccharomyces pombe is petite-negative, but some nuclear mutations enable the loss of its mitochondrial genome.
Results: Here, we characterize the classical petite-positive mutation ptp1-1 as a loss of function allele of the proteasome 19S regulatory subunit component mts4/rpn1, involved in the ubiquitin-dependent degradation pathway. By comparison with another petite-enabling mutation in the g-subunit of the F1-ATPase, we show that ptp1-1 does not rescue mitochondrial membrane potential. Instead, the mutation results in increased levels of mitochondrial and cytoplasmic chaperones and an altered oxidative stress response.
Conclusions: ptp1-1 is a partial loss of function mutation of the proteasome that enables growth of cells devoid of mitochondrial DNA through a mechanism that is independent of mitochondrial membrane potential rescue and associated with proteasome dependent regulation of mitochondrial protein import precursors and the oxidative stress response.
2025-08-15 | MSV000098838 | MassIVE
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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2024-09-02 | BIOMD0000000582 | BioModels
Project description:Pelleted non-perturbed LNCaP cells were lysed using LysisBuffer (8 M urea, 0.1 M ammonium bicarbonate, 0.1 % RapiGest) and nucleic acids sheared using sonication.
2018-01-22 | MSV000081956 | MassIVE
Project description:Defects in mitochondrial metabolism have been increasingly linked with age-onset protein misfolding diseases such as Alzheimerâs, Parkinsonâs, and Huntingtonâs. In response to protein folding stress, compartment-specific unfolded protein responses (UPRs) within the endoplasmic reticulum, mitochondria, and cytosol work in parallel to ensure cellular protein homeostasis. While perturbation of individual compartments can make other compartments more susceptible to protein stress, the cellular conditions that trigger cross-communication between the individual UPRs remain poorly understood. We have uncovered a conserved, robust mechanism linking mitochondrial protein homeostasis and the cytosolic folding environment through changes in lipid homeostasis. Metabolic restructuring caused by mitochondrial stress or small molecule activators trigger changes in gene expression coordinated uniquely by both the mitochondrial and cytosolic UPRs, protecting the cell from disease-associated proteins. Our data suggest an intricate and unique system of communication between UPRs in response to metabolic changes that could unveil new targets for diseases of protein misfolding. Because the induction of the MCSR due to hsp-6 RNAi required both hsf-1 and dve-1, key transcription factors required for the HSR and UPRmt, respectively, we asked which gene sets are coordinately regulated by both factors. We performed microarray analyses to determine which genes have their expression altered by hsp-6 RNAi and whether these genes are regulated either by hsf-1, dve-1 or both
2016-09-08 | E-GEOD-83722 | biostudies-arrayexpress
Project description:The dental pulp resides within a rigid dentin chamber with a limited blood supply, creating a hypoxic environment that impedes tissue regeneration. This study identifies intercellular mitochondrial transfer as a critical endogenous rescue mechanism. Human dental pulp stem cells (DPSCs) actively transfer functional mitochondria to green fluorescent protein-expressing human umbilical vein endothelial cells (GFP-ECs) under hypoxic stress. This transfer significantly reduces hypoxia-induced apoptosis, preserves mitochondrial membrane potential, and enhances the angiogenic capacities of recipient ECs. To uncover the molecular mechanisms driving this phenotype, RNA-sequencing (RNA-seq) was performed on mitochondrial-transferred ECs (Mito(+)) and control ECs (Mito(-)) under hypoxia.
2026-07-15 | GSE338573 | GEO
Project description:Background: Age-related macular degeneration (AMD) is a leading cause of vision loss. Reticular pseudodrusen (RPD), deposits on the apical side of the retinal pigment epithelium (RPE), signify a distinctive and critical AMD phenotype. Yet, their molecular basis and relationship to the conventional drusen seen in AMD remain unclear. Results: We generated induced pluripotent stem cell-derived RPE cells from a clinically phenotyped cohort comprising only individuals with conventional drusen (AMD/RPD-) or drusen coexisting with RPD (AMD/RPD+). From these cells, we generated single-cell transcriptomics, proteomics, and functional data to identify differences between the two cohorts. We show that AMD/RPD+ RPE cells exhibit enrichment in extracellular matrix (ECM) remodelling, cytoskeletal, and hypoxia-responsive programs, whereas AMD/RPD- RPE cells display a relatively greater representation of mitochondrial and protein homeostasis pathways. Both subtypes engaged pathways classically linked to ageing, including ECM remodelling and mitochondrial function, but differed in the direction and extent of these changes. Expression and protein quantitative trait loci (QTLs) highlight shared genetic influences on mitochondrial and iron-handling pathways, while disease-interacting eQTLs and transcriptome-wide association study identify regulatory signals that are distinctive of the RPD subtype within AMD, including through regulation of ECM. Functionally, all iPSC-derived RPE formed drusen-like deposits in vitro: AMD/RPD- lines generated more basal deposits, whereas AMD/RPD+ cells exhibited greater structural instability under bisretinoid-induced stress.
2026-04-09 | E-MTAB-16679 | biostudies-arrayexpress
Project description:Defects in mitochondrial metabolism have been increasingly linked with age-onset protein misfolding diseases such as Alzheimer’s, Parkinson’s, and Huntington’s. In response to protein folding stress, compartment-specific unfolded protein responses (UPRs) within the endoplasmic reticulum, mitochondria, and cytosol work in parallel to ensure cellular protein homeostasis. While perturbation of individual compartments can make other compartments more susceptible to protein stress, the cellular conditions that trigger cross-communication between the individual UPRs remain poorly understood. We have uncovered a conserved, robust mechanism linking mitochondrial protein homeostasis and the cytosolic folding environment through changes in lipid homeostasis. Metabolic restructuring caused by mitochondrial stress or small molecule activators trigger changes in gene expression coordinated uniquely by both the mitochondrial and cytosolic UPRs, protecting the cell from disease-associated proteins. Our data suggest an intricate and unique system of communication between UPRs in response to metabolic changes that could unveil new targets for diseases of protein misfolding.
2016-09-08 | GSE83722 | GEO