Homo sapiens
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA213007 | ENA |
REPOSITORIES: ENA
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Project description:How retinal pigmented epithelial (RPE) cells degenerate from oxidative stress in age-related macular degeneration (AMD) is incompletely understood. The study's intent was to identify key cytoprotective pathways activated by oxidative stress, and to determine the extent of their protection. Immunohistochemistry was used to identify the unfolded protein response (UPR) and mitochondria in the RPE of AMD samples. Maculas with early AMD had prominent IRE1α, but minimal mitochondrial TOM20 immunolabeling in mildly degenerated RPE. RPE cells treated with cigarette smoke extract (CSE), by microarray analysis, had over-represented genes involved in the antioxidant and unfolded protein response, and mitochondrial location. CSE induced the UPR sensors IRE1α, p-PERK, and ATP6, which activated CHOP. CHOP knockdown compromised cell viability after CSE exposure. At the same CSE doses, mitochondria generated superoxide anion and produced less ATP. In mice given intravitreal CSE, the RPE had increased IRE1α and decreased ATP, which elicited RPE epithelial-mesenchymal transition, as suggested by altered ZO1 immunolabeling of RPE flatmounts. Our experiments indicate that RPE cells exposed to oxidative stress respond with a cytoprotective antioxidant and unfolded protein response, but develop mitochondrial impairment that contributed to epithelial mesenchymal transition. With similar responses in the RPE of early AMD samples, these results suggest that mitochondria are vulnerable to oxidative stress while the ER elicits a protective response during early AMD. A total of 9 samples were analyzed: 3 control samples, 3 samples treated with 100ug/ml of Cigarette Smoke Condensate, and 3 samples treated with 250ug/ml of Cigarettes Smoke Condensate.
2014-01-30 | E-GEOD-49107 | biostudies-arrayexpress
Project description:How retinal pigmented epithelial (RPE) cells degenerate from oxidative stress in age-related macular degeneration (AMD) is incompletely understood. The study's intent was to identify key cytoprotective pathways activated by oxidative stress, and to determine the extent of their protection. Immunohistochemistry was used to identify the unfolded protein response (UPR) and mitochondria in the RPE of AMD samples. Maculas with early AMD had prominent IRE1α, but minimal mitochondrial TOM20 immunolabeling in mildly degenerated RPE. RPE cells treated with cigarette smoke extract (CSE), by microarray analysis, had over-represented genes involved in the antioxidant and unfolded protein response, and mitochondrial location. CSE induced the UPR sensors IRE1α, p-PERK, and ATP6, which activated CHOP. CHOP knockdown compromised cell viability after CSE exposure. At the same CSE doses, mitochondria generated superoxide anion and produced less ATP. In mice given intravitreal CSE, the RPE had increased IRE1α and decreased ATP, which elicited RPE epithelial-mesenchymal transition, as suggested by altered ZO1 immunolabeling of RPE flatmounts. Our experiments indicate that RPE cells exposed to oxidative stress respond with a cytoprotective antioxidant and unfolded protein response, but develop mitochondrial impairment that contributed to epithelial mesenchymal transition. With similar responses in the RPE of early AMD samples, these results suggest that mitochondria are vulnerable to oxidative stress while the ER elicits a protective response during early AMD.
2014-01-30 | GSE49107 | GEO
Project description:The mitochondrial unfolded protein response (UPRmt) is critical for protecting mitochondria against proteotoxic stress. Current UPRmt models propose that mitochondrial defects are detected by cytosolic surveillance mechanisms after release of damage into the cytosol. However, these findings are based on models that induce rapid and severe mitochondrial dysfunction, and thus their mode of toxicity contrasts sharply from physiologically occurring mitochondrial damage, e.g. the gradual accumulation of reactive oxygen species (ROS) during age-related decline or chronic respiratory chain defects. Here, we employed a chemogenetic strategy that induces low levels of H2O2 in the mitochondrial matrix to investigate cellular responses to physiologically relevant levels of mitochondrial dysfunction. We uncover that this mild oxidative stress activates the UPRmt independently of cytosolic signals revealing a so far concealed primary surveillance mechanism within mitochondria. Moreover, we identify the mitochondrial presequence proteases MPP and Oct1 as early molecular targets of ROS: Oxidative stress induces glutathionylation of critical cysteine residues, resulting in diminished proteolytic activity and the accumulation of proteotoxic precursor aggregates in the matrix. These aggregates are detected by intramitochondrial surveillance systems, activating UPRmt signaling. Our findings uncover the primary response to mitochondrial dysfunction, and highlight the organelle's capacity for self-surveillance and its ability to initiate early and rapid protective signaling in the face of mitochondrial dysfunction.
2026-04-20 | PXD077396 | Pride
Project description:The mitochondrial unfolded protein response (UPRmt) is critical for protecting mitochondria against proteotoxic stress. Current UPRmt models propose that mitochondrial defects are detected by cytosolic surveillance mechanisms after release of damage into the cytosol. However, these findings are based on models that induce rapid and severe mitochondrial dysfunction, and thus their mode of toxicity contrasts sharply from physiologically occurring mitochondrial damage, e.g. the gradual accumulation of reactive oxygen species (ROS) during age-related decline or chronic respiratory chain defects. Here, we employed a chemogenetic strategy that induces low levels of H2O2 in the mitochondrial matrix to investigate cellular responses to physiologically relevant levels of mitochondrial dysfunction. We uncover that this mild oxidative stress activates the UPRmt independently of cytosolic signals revealing a so far concealed primary surveillance mechanism within mitochondria. Moreover, we identify the mitochondrial presequence proteases MPP and Oct1 as early molecular targets of ROS: Oxidative stress induces glutathionylation of critical cysteine residues, resulting in diminished proteolytic activity and the accumulation of proteotoxic precursor aggregates in the matrix. These aggregates are detected by intramitochondrial surveillance systems, activating UPRmt signaling. Our findings uncover the primary response to mitochondrial dysfunction, and highlight the organelle's capacity for self-surveillance and its ability to initiate early and rapid protective signaling in the face of mitochondrial dysfunction.
2026-04-07 | PXD061965 | Pride
Project description:Caseinolytic protease X (ClpX) is an unfoldase that forms the ClpXP complex with caseinolytic protease P (ClpP), playing a critical role in maintaining mitochondrial protein homeostasis. While targeting ClpP has emerged as a promising cancer intervention strategy, the biological function of ClpX in cancer remains largely unexplored. In this study, we identify elevated expression of CLPX in pancreatic ductal adenocarcinoma (PDAC), which correlates with poor patient prognosis. CLPX knockdown significantly inhibits cell proliferation and disrupts mitochondrial protein homeostasis in PDAC cells. This knockdown also induces mitochondrial oxidative stress, impairs oxidative phosphorylation, and activates the unfolded protein response. CLPX knockdown increases reactive oxygen species (ROS) levels, ferrous ion accumulation, lipid peroxidation, and elevates malonaldehyde content, thus promoting ferroptosis. Furthermore, screening of reported ATPase inhibitors reveals that MSC1094308 binds to ClpX, inhibiting ClpXP-mediated substrate degradation. MSC1094308 induces unfolded protein stress and ferroptosis in PDAC cells. Altogether, our findings suggest that ClpX inhibition represents a potent therapeutic strategy for combating PDAC.
2026-01-28 | GSE289242 | GEO
Project description:The retinal pigmented epithelium (RPE) makes up the outer blood-retinal barrier, supports photoreceptor function of the eye and is constantly damaged by oxidative stress. Dysfunction of the RPE underlies pathology leading to development of age-related macular degeneration (AMD), the leading cause of vision loss among the elderly in industrialized nations. A major function of the RPE is to process photoreceptor outer segments which relies on the proper functioning of the RPE endocytic pathways and endosomal trafficking. RPE-released exosomes and other extracellular vesicles are essential parts of these pathways and may be early indicators of cellular stress. To test this, we used a polarized primary RPE cell culture model under chronic subtoxic oxidative stress to study the role of exosomes in the extracellular matrix (ECM) changes that underlie the early and late stages of AMD. Resulting unbiased proteomic analyses of highly purified basolateral exosomes from oxidatively stressed RPE cultures revealed changes to proteins involved in epithelial barrier integrity, that were detectable prior to overt cellular dysfunction. There were also changes to proteins accumulating in the basal-side sub-RPE ECM during oxidative stress, that could be prevented in the presence of an inhibitor of exosome release. We show for the first time that chronic subtoxic oxidative stress in primary RPE cultures induces proteomic changes in exosomes including basal-side specific desmosome and hemidesmosome shedding via exosomes. We also show that release of these exosomes correlates with ECM changes that can be partially prevented by inhibition of exosome release. These findings open a completely novel avenue for therapeutic intervention and access to early biomarkers of cellular dysfunction in aging-related retinal diseases, in particular AMD, and broadly from blood-CNS barriers in other neurodegenerative diseases.
2023-07-07 | MSV000092372 | MassIVE
Project description:To cope with a challenging and unpredictable environment, living systems have evolved several organelle-specific stress responses, e.g. the cytosolic heat shock response (HSR), the endoplasmic reticulum unfolded protein response (UPRER) and the mitochondrial unfolded protein response (UPRmt). UPRmt monitors mitochondrial function and homeostasis in general. However, the mechanism of UPRmt remains largely unexplored. Here we identified that histone deacetylase HDA-1 is associated with homeobox domain-containing protein DVE-1 in UPRmt activation in Caenorhabditis elegans. Knocking down ATP synthase subunit atp-2 generates mitochondrial stress and induces UPRmt. After analyzing the mRNA profiles of worms on L4440 RNAi, hda-1 RNAi or dve-1 RNAi and untreated or treated with atp-2 RNAi, we found that 283 hda-1_dependent genes and 218 dve-1_dependent genes were upregulated in response to atp-2 RNAi.
2020-07-19 | GSE141041 | GEO
Project description:The mitochondrial matrix is unique in that it must integrate folding and assembly of proteins derived from nuclear and mitochondrial genomes. In C. elegans, the mitochondrial unfolded protein response (UPRmt) senses matrix protein misfolding and induces a program of nuclear gene expression, including mitochondrial chaperonins, to promote mitochondrial proteostasis. While misfolded mitochondrial matrix-localized ornithine trans-carbamylase (OTC) induces chaperonin expression, our understanding of mammalian UPRmt is rudimentary, reflecting a lack of acute triggers for UPRmt activation. This limitation has prevented analysis of the cellular responses to matrix protein misfolding and the effects of UPRmt on mitochondrial translation to control protein folding loads. Here, we combine pharmacological inhibitors of matrix-localized HSP90/TRAP1 or LON protease, which promote chaperonin expression, with global transcriptional and proteomic analysis to reveal an extensive and acute response of human cells to UPRmt. This response involved widespread induction of nuclear genes, including matrix-localized proteins involved in folding, pre-RNA processing and translation. Functional studies revealed rapid but reversible translation inhibition in mitochondria occurring concurrently with defects in pre-RNA processing due to transcriptional repression and LON-dependent turnover of the mitochondrial pre-RNA processing nuclease MRPP3. This study reveals that acute mitochondrial protein folding stress activates both increased chaperone availability within the matrix and reduced matrix-localized protein synthesis through translational inhibition, and provides a framework for further dissection of mammalian UPRmt. triplicate experiment of 3 conditions (untreated, GTPP treatment, CDDO treatment)
2016-06-28 | E-GEOD-75247 | biostudies-arrayexpress
Project description:The mitochondrial matrix is unique in that it must integrate folding and assembly of proteins derived from nuclear and mitochondrial genomes. In C. elegans, the mitochondrial unfolded protein response (UPRmt) senses matrix protein misfolding and induces a program of nuclear gene expression, including mitochondrial chaperonins, to promote mitochondrial proteostasis. While misfolded mitochondrial matrix-localized ornithine trans-carbamylase (OTC) induces chaperonin expression, our understanding of mammalian UPRmt is rudimentary, reflecting a lack of acute triggers for UPRmt activation. This limitation has prevented analysis of the cellular responses to matrix protein misfolding and the effects of UPRmt on mitochondrial translation to control protein folding loads. Here, we combine pharmacological inhibitors of matrix-localized HSP90/TRAP1 or LON protease, which promote chaperonin expression, with global transcriptional and proteomic analysis to reveal an extensive and acute response of human cells to UPRmt. This response involved widespread induction of nuclear genes, including matrix-localized proteins involved in folding, pre-RNA processing and translation. Functional studies revealed rapid but reversible translation inhibition in mitochondria occurring concurrently with defects in pre-RNA processing due to transcriptional repression and LON-dependent turnover of the mitochondrial pre-RNA processing nuclease MRPP3. This study reveals that acute mitochondrial protein folding stress activates both increased chaperone availability within the matrix and reduced matrix-localized protein synthesis through translational inhibition, and provides a framework for further dissection of mammalian UPRmt. triplicate experiment of 2 conditions (untreated, GTPP treatment)
2016-06-28 | E-GEOD-75410 | biostudies-arrayexpress
Project description:Age-related macular degeneration (AMD) is a leading cause of vision loss in the elderly, driven by retinal pigment epithelium (RPE) dysfunction, mitochondrial impairment, oxidative stress, chronic inflammation, and cellular senescence. Vutiglabridin, an orally available derivative of glabridin, has been reported to enhance mitochondrial function and mitigate metabolic stress, suggesting potential therapeutic utility in retinal aging. Here, we evaluated the efficacy and mechanism of Vutiglabridin in multiple models, including naturally aged mice representing age-associated retinal degeneration, sodium iodate (NaIO3)-induced geographic atrophy (GA), and laser-induced choroidal neovascularization (CNV). Retinal morphology and function were assessed by fundus photography, autofluorescence imaging, and electroretinography, while molecular, histological, and transcriptomic analyses were employed to investigate senescence, mitochondrial function, and inflammation. Pharmacokinetic profiling demonstrated prolonged ocular distribution of Vutiglabridin. In parallel, Paraoxonase 2 (PON2) knockdown mice were used to determine the mechanistic dependency. Vutiglabridin attenuated senescence and inflammatory markers, reduced mitochondrial ROS, and preserved retinal thickness in aged mice, while bulk RNA sequencing demonstrated partial reversal of aging-associated transcriptional signatures. In the NaIO3 model, Vutiglabridin restored mitochondrial membrane potential, enhanced mitophagy, and improved retinal function. In CNV models, it suppressed lesion growth and oxidative stress with efficacy comparable to aflibercept. Importantly, Vutiglabridin increased PON2 protein levels in vivo, and its protective effects were abolished in PON2-deficient mice, confirming a PON2-dependent mechanism. These findings establish Vutiglabridin as a promising oral therapeutic candidate for both dry and neovascular AMD, acting through PON2-mediated enhancement of mitochondrial resilience and suppression of oxidative, inflammatory, and senescent pathways.
2025-09-19 | GSE307930 | GEO