Lost in Translation: Endoplasmic Reticulum-Mitochondria Crosstalk in Idiopathic Pulmonary Fibrosis.
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ABSTRACT:
SUBMITTER: Bueno M
PROVIDER: S-EPMC7528920 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:The molecular pathomechanisms underlying idiopathic pulmonary fibrosis (IPF) are elusive, but chronic epithelial injury has recently been suggested as key event.We investigated the possible implication of endoplasmic reticulum (ER) stress-mediated apoptosis in sporadic IPF.We 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.Compared 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).Severe 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.
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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.
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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.
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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.
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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.
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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.
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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.
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Project description:Idiopathic normal pressure hydrocephalus (iNPH) is a neuropathology with unknown cause characterised by gait impairment, cognitive decline and ventriculomegaly. These patients often present comorbidity with Alzheimer's disease (AD), including AD pathological hallmarks such as amyloid plaques mainly consisting of amyloid β-peptide and neurofibrillary tangles consisting of hyperphosphorylated tau protein. Even though some of the molecular mechanisms behind AD are well described, little is known about iNPH. Several studies have reported that mitochondria-endoplasmic reticulum contact sites (MERCS) regulate amyloid β-peptide metabolism and conversely that amyloid β-peptide can influence the number of MERCS. MERCS have also been shown to be dysregulated in several neurological pathologies including AD.In this study we have used transmission electron microscopy and show, for the first time, several mitochondria contact sites including MERCS in human brain biopsies. These unique human brain samples were obtained during neurosurgery from 14 patients that suffer from iNPH. Three of these 14 patients presented comorbidities with other dementias: one patient with AD, one with AD and vascular dementia and one patient with Lewy body dementia. Furthermore, we report that the numbers of MERCS are increased in biopsies obtained from patients diagnosed with dementia. Moreover, the presence of both amyloid plaques and neurofibrillary tangles correlates with decreased contact length between endoplasmic reticulum and mitochondria, while amyloid plaques alone do not seem to affect endoplasmic reticulum-mitochondria apposition. Interestingly, we report a significant positive correlation between the number of MERCS and ventricular cerebrospinal fluid amyloid β-peptide levels, as well as with increasing age of iNPH patients.
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