Lost in Translation: Endoplasmic Reticulum-Mitochondria Crosstalk in Idiopathic Pulmonary Fibrosis.
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ABSTRACT:
SUBMITTER: Bueno M
PROVIDER: S-EPMC7528920 | biostudies-literature | 2020 Oct
REPOSITORIES: biostudies-literature
Publications
Lost in Translation: Endoplasmic Reticulum-Mitochondria Crosstalk in Idiopathic Pulmonary Fibrosis.
Bueno Marta M Rojas Mauricio M
American journal of respiratory cell and molecular biology 20201001 4
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Project description:RationaleThe molecular pathomechanisms underlying idiopathic pulmonary fibrosis (IPF) are elusive, but chronic epithelial injury has recently been suggested as key event.ObjectivesWe investigated the possible implication of endoplasmic reticulum (ER) stress-mediated apoptosis in sporadic IPF.MethodsWe analyzed peripheral explanted lung tissues from patients with sporadic IPF (n = 24), chronic obstructive pulmonary disease (COPD) (n = 9), and organ donors (n = 12) for expression of major ER stress mediators and apoptosis markers by means of immunoblotting, semiquantitative reverse transcription-polymerase chain reaction, immunohistochemistry, and the TUNEL method.Measurements and main resultsCompared with COPD and donor lungs, protein levels of ER stress mediators, such as processed p50 activating transcription factor (ATF)-6 and ATF-4 and the apoptosis-inductor CHOP (C/EBP-homologous protein), as well as transcript levels of spliced X-box binding protein (XBP)-1, were significantly elevated in lung homogenates and type II alveolar epithelial cells (AECIIs) of IPF lungs. Proapoptotic, oligomeric forms of Bax, which play a key role in ER stress-mediated apoptosis downstream of CHOP induction, as well as caspase-3 cleavage, could be detected in IPF lungs. By means of immunohistochemistry, exclusive induction of active ATF-6, ATF-4, and CHOP in AECIIs was encountered in IPF but not in COPD or donor lungs. Immunoreactivity was most prominent in the epithelium near dense zones of fibrosis and fibroblast foci, where these ER stress markers colocalized with markers of apoptosis (TUNEL, cleaved caspase-3).ConclusionsSevere ER stress response in the AECIIs of patients with sporadic IPF may underlie the apoptosis of this cell type and development of fibrosis in this disease.
| S-EPMC2566794 | biostudies-literature
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.
2025-08-31 | GSE305514 | GEO
Project description:Alveolar epithelial type II (AEII) cells are "professional" secretory cells that synthesize and secrete massive quantities of proteins to produce pulmonary surfactant and maintain airway immune defenses. To facilitate this high level of protein synthesis, AEII cells are equipped with an elaborate endoplasmic reticulum (ER) structure and possess an abundance of the machinery needed to fold, assemble, and secrete proteins. However, conditions that suddenly increase the quantity of new proteins entering the ER or that impede the capacity of the ER to fold proteins can cause misfolded or unfolded proteins to accumulate in the ER lumen, also called ER stress. To minimize this stress, AEII cells adapt by (1) reducing the quantity of proteins entering the ER, (2) increasing the amount of protein-folding machinery, and (3) removing misfolded proteins when they accumulate. Although these adaptive responses, aptly named the unfolded protein response, are usually effective in reducing ER stress, chronic aggregation of misfolded proteins is recognized as a hallmark feature of AEII cells in patients with idiopathic pulmonary fibrosis (IPF). Although mutations in surfactant proteins are linked to the development of ER stress in some rare IPF cases, the mechanisms causing protein misfolding in most cases are unknown. In this article, we review the mechanisms regulating ER proteostasis and highlight specific aspects of protein folding and the unfolded protein response that are most vulnerable to failure. Then, we postulate mechanisms other than genetic mutations that might contribute to protein aggregation in the alveolar epithelium of IPF lung.
| S-EPMC5711273 | biostudies-literature
Project description:A Ca(2+) signaling model is proposed to consider the crosstalk of Ca(2+) ions between endoplasmic reticulum (ER) and mitochondria within microdomains around inositol 1, 4, 5-trisphosphate receptors (IP3R) and the mitochondrial Ca(2+) uniporter (MCU). Our model predicts that there is a critical IP3R-MCU distance at which 50% of the ER-released Ca(2+) is taken up by mitochondria and that mitochondria modulate Ca(2+) signals differently when outside of this critical distance. This study highlights the importance of the IP3R-MCU distance on Ca(2+) signaling dynamics. The model predicts that when MCU are too closely associated with IP3Rs, the enhanced mitochondrial Ca(2+) uptake will produce an increase of cytosolic Ca(2+) spike amplitude. Notably, the model demonstrates the existence of an optimal IP3R-MCU distance (30-85 nm) for effective Ca(2+) transfer and the successful generation of Ca(2+) signals in healthy cells. We suggest that the space between the inner and outer mitochondria membranes provides a defense mechanism against occurrences of high [Ca(2+)]Cyt. Our results also hint at a possible pathological mechanism in which abnormally high [Ca(2+)]Cyt arises when the IP3R-MCU distance is in excess of the optimal range.
| S-EPMC4303883 | biostudies-literature
Project description:This study was designed to investigate the mechanism by which MMDD improves lung function, and observe the effect of MMDD on endoplasmic reticulum stress(ERS) in alveolar type II epithelial cells (AECIIs) of pulmonary fibrosis rats. pulmonary fibrosis animal model was established by intratracheal injection of BLM at a dose of 6mg/kg body weight. Overall, Thirty male SPF Sprague-Dawley rats were randomly divided into control group, BLM group and BLM+MMDD group. BLM+MMDD group rats were fed 24 g/kg over three weeks for twice a day on the fourteenth day after model establishment. MMDD improves pulmonary function of fibrotic rats and reduces the occurrence of endoplasmic reticulum stress in AECIIs. MMDD could significantly improve the forced vital capacity (FVC) of bleomycin-induced pulmonary fibrosis in rats. MMDD reduced the expression of GRP78 and CHOP in AECIIs, increased the secretion of surfactant protein C (SPC) by AECIIs. Moreover, the apoptosis of the fibrosis zone in the lung tissue was remarkably mitigated by administration of MMDD. The finding of this study revealed that MMDD can improve lung function in rats with pulmonary fibrosis by reducing the occurrence of ERS and cell apoptosis of AECIIs. It may provide a new method for the treatment of pulmonary fibrosis.
| S-EPMC7466437 | biostudies-literature
Project description:Beta-cell destruction in type 1 diabetes (T1D) results from the combined effect of inflammation and recurrent autoimmunity. In response to inflammatory signals, beta-cells engage adaptive mechanisms where the endoplasmic reticulum (ER) and mitochondria act in concert to restore cellular homeostasis. In the recent years it has become clear that this adaptive phase may trigger the development of autoimmunity by the generation of autoantigens recognized by autoreactive CD8 T cells. The participation of the ER stress and the unfolded protein response to the increased visibility of beta-cells to the immune system has been largely described. However, the role of the other cellular organelles, and in particular the mitochondria that are central mediator for beta-cell survival and function, remains poorly investigated. In this review we will dissect the crosstalk between the ER and mitochondria in the context of T1D, highlighting the key role played by this interaction in beta-cell dysfunctions and immune activation, especially through regulation of calcium homeostasis, oxidative stress and generation of mitochondrial-derived factors.
| S-EPMC8085402 | biostudies-literature
Project description:BackgroundIdiopathic pulmonary fibrosis (IPF) is a chronic progressive interstitial lung disease. This study aimed to investigate the involvement of endoplasmic reticulum stress (ERS) in IPF and explore its correlation with immune infiltration.MethodsERS-related differentially expressed genes (ERSRDEGs) were identified by intersecting differentially expressed genes (DEGs) from three Gene Expression Omnibus datasets with ERS-related gene sets. Gene Set Variation Analysis and Gene Ontology were used to explore the potential biological mechanisms underlying ERS. A nomogram was developed using the risk signature derived from the ERSRDEGs to perform risk assessment. The diagnostic value of the risk signature was evaluated using receiver operating characteristics, calibration, and decision curve analyses. The ERS score of patients with IPF was measured using a single-sample Gene Set Enrichment Analysis (ssGSEA) algorithm. Subsequently, a prognostic model based on the ERS scores was established. The proportion of immune cell infiltration was assessed using the ssGSEA and CIBERSORT algorithms. Finally, the expression of ERSRDEGs was validated in vivo and in vitro via RT-qPCR.ResultsThis study developed an 8-ERSRDEGs signature. Based on the expression of these genes, we constructed a diagnostic nomogram model in which agouti-related neuropeptide had a significantly greater impact on the model. The area under the curve values for the predictive value of the ERSRDEGs signature were 0.975 and 1.000 for GSE70866 and GSE110147, respectively. We developed a prognostic model based on the ERS scores of patients with IPF. Furthermore, we classified patients with IPF into two subtypes based on their signatures. The RT-qPCR validation results supported the reliability of most of our conclusions.ConclusionWe developed and verified a risk model using eight ERSRDEGs. These eight genes can potentially affect the progression of IPF by regulating ERS and immune responses.
| S-EPMC10808546 | biostudies-literature
Project description:Pulmonary fibrosis and emphysema are irreversible chronic events after inhalation injury. However, the mechanism(s) involved in their development remain poorly understood. Higher levels of plasma and lung heme have been recorded in acute lung injury associated with several insults. Here, we provide the molecular basis for heme-induced chronic lung injury. We found elevated plasma heme in chronic obstructive pulmonary disease (COPD) (GOLD stage 4) patients and also in a ferret model of COPD secondary to chronic cigarette smoke inhalation. Next, we developed a rodent model of chronic lung injury, where we exposed C57BL/6 mice to the halogen gas, bromine (Br2) (400 ppm, 30 minutes), and returned them to room air resulting in combined airway fibrosis and emphysematous phenotype, as indicated by high collagen deposition in the peribronchial spaces, increased lung hydroxyproline concentrations, and alveolar septal damage. These mice also had elevated pulmonary endoplasmic reticulum (ER) stress as seen in COPD patients; the pharmacological or genetic diminution of ER stress in mice attenuated Br2-induced lung changes. Finally, treating mice with the heme-scavenging protein, hemopexin, reduced plasma heme, ER stress, airway fibrosis, and emphysema. This is the first study to our knowledge to report elevated heme in COPD patients and establishes heme scavenging as a potential therapy after inhalation injury.
| S-EPMC6238745 | biostudies-literature
Project description:BackgroundIdiopathic Pulmonary Fibrosis (IPF) presents a severe respiratory challenge with a poor prognosis due to the lack of reliable biomarkers. Recent evidence suggests that Endoplasmic Reticulum Stress (ERS) may be associated with IPF pathogenesis. This study focuses on uncovering ERS-associated biomarkers for IPF.MethodsSequencing data from diverse datasets were analyzed, utilizing differential gene expression analysis and Weighted Gene Co-expression Network Analysis (WGCNA). Endoplasmic Reticulum Stress (ERS)-related genes were extracted from the GeneCards database. Hub genes were identified through Protein-Protein Interaction (PPI) analysis. Diagnostic and prognostic models were developed using machine learning algorithms and validated across both training and validation sets. Additionally, techniques such as Cell-type Identification by Estimating Relative Subsets of RNA Transcripts and single-cell RNA sequencing were employed to identify potential IPF-related cells. These findings were further investigated to elucidate their underlying mechanisms through in vitro experiments.ResultsDifferentially expressed genes, WGCNA-identified blue module genes, and ERS-related genes extracted from the GeneCards database were intersected, and the resulting genes were used to construct diagnostic and prognostic models. Validation using multiple datasets indicated that both the diagnostic and prognostic models possess strong predictive capabilities. PPI analysis highlighted SPP1 as a potential hub gene in IPF. Moreover, M2 macrophages were found in higher quantities in the lung tissue of IPF patients, with a significant increase in SPP1-expressing M2 macrophages compared to the control group. In vitro experiments demonstrated that exogenous SPP1 inhibited the proliferation and migration of M2 macrophages and promoted apoptosis within a certain concentration range.ConclusionThis study identifies ERS-related biomarkers in IPF, highlighting SPP1 and M2 macrophages. The resulting diagnostic and prognostic models offer strong predictive capabilities, unveiling new therapeutic avenues.
| S-EPMC11441044 | biostudies-literature
Project description:The functional status of mitochondria and the endoplasmic reticulum are central to renal ischemia/reperfusion injury (IRI). X-box binding protein 1 (XBP1) is an important transcription factor in endoplasmic reticulum stress. NLR family pyrin domain containing-3 (NLRP3) inflammatory bodies are closely related to renal IRI. In vivo and in vitro, we examined the molecular mechanisms and functions of XBP1-NLRP3 signaling in renal IRI, which influences ER-mitochondrial crosstalk. In this study, mice were subjected to 45 min of unilateral renal warm ischemia, the other kidney resected, and reperfusion was performed for 24 h in vivo. In vitro, murine renal tubular epithelial cells (TCMK-1) were exposed to hypoxia for 24 h and reoxygenation for 2 h. Tissue or cell damage was evaluated by measuring blood urea nitrogen and creatinine levels, histological staining, flow cytometry, terminal deoxynucleotidyl transferase-mediated nick-end labeling, diethylene glycol staining, and transmission electron microscopy (TEM). Western blotting, immunofluorescence staining, and ELISA were used to analyze protein expression. Whether XBP1 regulates the NLRP3 promoter was evaluated using a luciferase reporter assay. Kidney damage was reduced with decreasing blood urea nitrogen, creatinine, interleukin-1β, and interleukin-18 levels. XBP1 deficiency reduced tissue damage and cell apoptosis, protecting the mitochondria. Disruption of XBP1 was associated with reduced NLRP3 and cleaved caspase-1 levels and markedly improved survival. In vitro in TCMK-1 cells, XBP1 interference inhibited caspase-1-dependent mitochondrial damage and reduced the production of mitochondrial reactive oxygen species. The luciferase assay showed that spliced XBP1 isoforms enhanced the activity of the NLRP3 promoter. These findings reveal that XBP1 downregulation suppresses the expression of NLRP3, a potential regulator of endoplasmic reticulum mitochondrial crosstalk in nephritic injury and a potential therapeutic target in XBP1-mediated aseptic nephritis.
| S-EPMC9938143 | biostudies-literature