Excessive sulfur oxidation in endoplasmic reticulum drives an inflammatory reaction of chondrocytes in aging mice
Ontology highlight
ABSTRACT:
ORGANISM(S): Mus Musculus
SUBMITTER: 
Kun Chen
PROVIDER: PXD037302 | iProX | Wed Oct 12 00:00:00 BST 2022
REPOSITORIES: iProX
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Project description:Background: Chondrocyte homeostasis is vital for maintaining the extracellular matrix (ECM) and overall cartilage health. In osteoarthritis (OA), oxidative stress, often caused by redox imbalances, can disrupt chondrocyte homeostasis, leading to cartilage degradation. Hydrogen peroxide (H2O2), a reactive oxygen species (ROS), is a key mediator of oxidative stress and contributes to chondrocyte apoptosis and ECM degradation. Previous studies have explored individual protein responses to oxidative stress; however, a comprehensive proteomic analysis in chondrocytes has not been conducted. In this study, we aimed to assess the global proteomic alterations in chondrocytes exposed to H2O2 using a shotgun proteomics approach, which enables the detection of a broader spectrum of proteomic changes. Methods: Chondrocytes were treated with H2O2 for 1, 4, and 16 h followed by protein extraction and processing, including denaturation, alkylation, and trypsin digestion. The peptides were then acidified, desalted, dried, and resuspended for LC-MS/MS. Proteomics data were analyzed using MaxQuant software to identify and quantify proteins. Secretome analysis was performed to examine protein secretion changes under oxidative stress. The statistical significance of all proteomics and secretome data was assessed using a two-tailed Student’s t-test in the Perseus software. Complementary methods, including quantitative PCR, western blotting, and immunofluorescence, were employed to validate the proteomic analysis. Results: Our findings revealed that oxidative stress primarily affected the endoplasmic reticulum (ER), causing notable alterations in the expression of ER-associated proteins, redox-responsive enzymes, chaperones, and sialyltransferases. These changes increased intracellular accumulation of ECM proteins and decreased secretion into the extracellular environment, indicating impaired protein trafficking and secretion. Additionally, immune-related pathways were activated in the long term, with a short-term upregulation of inflammatory markers, such as interleukin (IL)-6) and IL-18, although the levels of matrix metalloproteinases (MMPs) remained stable, indicating a complex inflammatory response and stress responses that disrupt ECM homeostasis. Conclusions: Our study demonstrates a detailed proteomic view of the stress response of H2O2-treated chondrocytes, highlighting the significant changes in ER function, cytoskeletal remodeling, protein secretion, and immune responses. These changes suggest that oxidative stress impacts ECM balance and contributes to OA progression, offering new insights into the molecular mechanisms underlying oxidative stress in OA.
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Project description:Osteoarthritis is a prevalent joint disease in the aging population. The hallmark of osteoarthritis is the degeneration of the joint cartilage, characterized by changes in chondrocytes including mitochondrial dysfunction. However, the precise mechanisms of how this affects chondrocyte homeostasis and whether such processes can be explored as therapeutic targets for osteoarthritis remain unclear. Here, we show that impaired mitochondrial function and disrupted cartilage matrix metabolism due to loss of mitofusin-2 (MFN2) expression in chondrocytes leads to the development of osteoarthritis. Sirtuin-3 (SIRT3), a key regulator of mitochondrial function, plays a critical role in modulating MFN2 to restore mitochondrial dynamics, reduce fragmentation, and preserve mitochondrial function in chondrocytes. Specifically, SIRT3 directly deacetylates and indirectly deubiquitinates MFN2, preventing its degradation. MFN2-mediated mitochondrial–endoplasmic reticulum (ER) junctions support cellular homeostasis, alleviate ER stress, and maintain mitochondrial calcium ion balance, which collectively mitigate chondrocyte senescence. Extracellular vesicles engineered with MFN2 mRNA effectively prevented cartilage degeneration and restored mobility in osteoarthritic mice. These findings suggest that targeting MFN2 is a promising strategy to prevent cartilage degeneration and alleviate progression of osteoarthritis.
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Project description:Natural and anthropogenic wetlands are main sources of the atmospheric greenhouse gas methane. Methane emissions from wetlands are mitigated by methanotrophic microorganisms and by processes at the oxic-anoxic interface, such as sulfur cycling, that reduce the activity of methanogens. In this study, we obtained a pure culture (strain HY1) of a versatile wetland methanotroph that oxidizes various organic and inorganic compounds. This strain represents (i) the first isolate that can aerobically oxidize both methane and reduced sulfur compounds and (ii) a new alphapoteobacterial species, named Candidatus Methylovirgula thiovorans. Genomic and proteomic analyses showed that soluble methane monooxygenase and XoxF-type alcohol dehydrogenases are the only enzymes for methane and methanol oxidation, respectively. Unexpectedly, strain HY1 harbors various pathways for respiratory sulfur oxidation and oxidized reduced sulfur compounds to sulfate using the Sox-rDsr pathway (without SoxCD) and the S4I system. It employed the Calvin-Benson-Bassham cycle for CO2 fixation during chemolithoautotrophic growth on the reduced sulfur compounds. Methane and thiosulfate were independently and simultaneously oxidized by strain HY1 for growth. Proteomic and microrespiratory analyses showed that the metabolic pathways for methane and thiosulfate oxidation were induced in the presence of their substrates. The discovery of this versatile methanotroph demonstrates that methanotrophy and thiotrophy is compatible in a single bacterium and adds a new aspect to interactions of methane and sulfur cycles in oxic-anoxic interface environments.
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Project description:Responses of photosynthetic organisms to sulfur starvation include (i) increasing the capacity of the cell for transporting and/or assimilating exogenous sulfate, (ii) restructuring cellular features to conserve sulfur resources, and (iii) modulating metabolic processes and rates of cell growth and division. We used microarray analyses to obtain a genome-level view of changes in mRNA abundances in the green alga Chlamydomonas reinhardtii during sulfur starvation. The work confirms and extends upon previous findings showing that sulfur deprivation elicits changes in levels of transcripts for proteins that help scavenge sulfate and economize on the use of sulfur resources. Changes in levels of transcripts encoding members of the light-harvesting polypeptide family, such as LhcSR2, suggest restructuring of the photosynthetic apparatus during sulfur deprivation. There are also significant changes in levels of transcripts encoding enzymes involved in metabolic processes (e.g., carbon metabolism), intracellular proteolysis, and the amelioration of oxidative damage; a marked and sustained increase in mRNAs for a putative vanadium chloroperoxidase and a peroxiredoxin may help prolong survival of C. reinhardtii during sulfur deprivation. Furthermore, many of the sulfur stress-regulated transcripts (encoding polypeptides associated with sulfate uptake and assimilation, oxidative stress, and photosynthetic function) are not properly regulated in the sac1 mutant of C. reinhardtii, a strain that dies much more rapidly than parental cells during sulfur deprivation. Interestingly, sulfur stress elicits dramatic changes in levels of transcripts encoding putative chloroplast-localized chaperones in the sac1 mutant but not in the parental strain. These results suggest various strategies used by photosynthetic organisms during acclimation to nutrient-limited growth. An all pairs experiment design type is where all labeled extracts are compared to every other labeled extract. Keywords: all_pairs
2005-07-28 | GSE3015 | GEO
Project description:Chemosynthetic symbioses occur worldwide in marine habitats, but comprehensive physiological studies of chemoautotrophic bacteria thriving on animals are scarce. Stilbonematinae are coated by monocultures of thiotrophic Gammaproteobacteria. As these nematodes migrate through the redox zone, their ectosymbionts experience varying oxygen concentrations. Here, by applying omics, Raman microspectroscopy and stable isotope labeling, we investigated the effect of oxygen on the metabolism of Candidatus Thiosymbion oneisti. Unexpectedly, sulfur oxidation genes were upregulated in anoxic relative to oxic conditions, but carbon fixation genes and incorporation of 13C-labeled bicarbonate were not. Instead, several genes involved in carbon fixation, organic carbon assimilation and polyhydroxyalkanoate (PHA) biosynthesis, as well as nitrogen fixation and urea utilization were upregulated in oxic conditions. Furthermore, in the presence of oxygen, stress-related genes were upregulated together with vitamin biosynthesis genes likely necessary to withstand its deleterious effects, and fewer symbionts were detected to divide. Based on this first global physiological study of an uncultured chemosynthetic ectosymbiont, we propose that, in anoxic sediment, its proliferation is powered by anaerobic sulfur oxidation coupled to denitrification, whereas in upper layers it makes use of aerobic respiration to facilitate assimilation of carbon and nitrogen, and to survive oxidative stress. The ectosymbiont’s versatile metabolism is thus well-adapted to exploiting a highly changeable environment.
2020-04-30 | GSE146081 | GEO