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Antioxidants & Redox Signaling Jan 2024This study investigated the regulatory effect of Mitofusin2 (Mfn2) on mitochondria-associated endoplasmic reticulum membrane (MAM) integrity and cellular injury in...
Mitofusin2 Ameliorated Endoplasmic Reticulum Stress and Mitochondrial Reactive Oxygen Species Through Maintaining Mitochondria-Associated Endoplasmic Reticulum Membrane Integrity in Cisplatin-Induced Acute Kidney Injury.
This study investigated the regulatory effect of Mitofusin2 (Mfn2) on mitochondria-associated endoplasmic reticulum membrane (MAM) integrity and cellular injury in cisplatin-induced acute kidney injury (CP-AKI). CP-AKI mice exhibited decreased expression of Mfn2, increased expression of phosphorylated adenosine monophosphate-activated protein kinase (p-AMPK), abnormal mitochondrial morphology, and reduced MAMs integrity, accompanied by the activation of mitochondrial reactive oxygen species (ROS) and endoplasmic reticulum (ER) stress (inositol-requiring enzyme 1 [IRE1] and PERK pathways). In studies, CP-induced mitochondrial ROS, ER-stress activation, and increased apoptosis were accompanied by the downregulation of Mfn2 and MAMs integrity reduction in Boston University mouse proximal tubular cells (BUMPT) and human proximal tubular epithelial cells (HK-2). Pretreatment of BUMPT cells with the Mfn2 plasmid partially restored the integrity of MAMs, negatively controlled IRE1 and PERK pathways, and inhibited cell apoptosis. In contrast, ER-stress and MAMs integrity violations were increased after Mfn2 small-interfering RNA (siRNA) treatment in HK-2 cells under CP treatment. Coimmunoprecipitation analysis demonstrated that Mfn2 interacted with PERK and IRE1. Furthermore, the adenosine 5'-monophosphate (AMP)-activated protein kinase (AMPK), acadesine (AICAR), had a similar effect to Mfn2 plasmid in the regulation of ER stress and MAMs. Conversely, the ER-stress inhibitor, 4-phenylbutyric acid (4-PBA), had no effect on the expression of Mfn2 and MAMs integrity. This is the first study to explore the association between MAMs, ER stress, and Mfn2 in CP-AKI. Downregulation of Mfn2 expression abolished the MAMs integrity, and induced ER stress, mitochondrial ROS, and tubular cell apoptosis. This suggests that the Mfn2-MAMs pathway is a potential therapeutic target in CP-AKI. 40, 16-39. The Ethical Registration number of animal experiment in this study was CSU-2022-01-0095.
Topics: Mice; Humans; Animals; Reactive Oxygen Species; Cisplatin; AMP-Activated Protein Kinases; Protein Serine-Threonine Kinases; Endoplasmic Reticulum Stress; Mitochondria; Endoplasmic Reticulum; Apoptosis; Acute Kidney Injury
PubMed: 37053105
DOI: 10.1089/ars.2022.0178 -
Archives of Razi Institute Oct 2023Most chemicals expressed in mammalian cells have complex delivery and transport mechanisms to get to the right intracellular sites. One of these mechanisms transports... (Review)
Review
Most chemicals expressed in mammalian cells have complex delivery and transport mechanisms to get to the right intracellular sites. One of these mechanisms transports most transmembrane proteins, as well as almost all secreted proteins, from the endoplasmic reticulum, where they are formed, to their final location. Nearly all eukaryotic cells have a membrane trafficking mechanism that is both a prominent and critical component. This system, which consists of dynamically coupled compartments, supports the export and uptake of extracellular material, remodeling and signaling at the cellular interface, intracellular alignment, and maintenance of internal compartmentalization (organelles). In animal cells, this system enables both regular cellular activities and specialized tasks, such as neuronal transmission and hormone control. Human diseases, including neurodegenerative diseases, such as Alzheimer's disease, heart disease, and cancer, are associated with the dysfunction or dysregulation of the membrane trafficking system. Treatment and cure of human diseases depends on understanding the cellular and molecular principles underlying membrane trafficking pathways. A single gene mutation or mutations that result in impaired membrane trafficking cause a range of clinical disorders that are the result of changes in cellular homeostasis. Other eukaryotic organisms with significant economic and agricultural value, such as plants and fungi, also depend on the membrane trafficking system for their survival. In this review, we focused on the major human diseases associated with the process of membrane trafficking, providing a broad overview of membrane trafficking.
Topics: Animals; Humans; Endoplasmic Reticulum; Neurodegenerative Diseases; Mammals
PubMed: 38590688
DOI: 10.22092/ARI.2023.78.5.1397 -
Cells Aug 2023Phytoplasmas are intracellular plant pathogens that heavily rely on host cell nutrients for survival and propagation due to their limited ability to synthesize essential...
Phytoplasmas are intracellular plant pathogens that heavily rely on host cell nutrients for survival and propagation due to their limited ability to synthesize essential substrates. The endoplasmic reticulum (ER), which plays a vital role in various cellular processes, including lipid and protein biosynthesis, is an attractive target for numerous intracellular pathogens to exploit. This study investigated the impact of potato purple top (PPT) phytoplasma infection on the ER in tomato plants. Abnormal accumulation of ER-resident proteins, disrupted ER network structures, and formation of protein aggregates in the phloem were observed using confocal microscopy and transmission electron microscopy, indicating a phytoplasma-infection-induced disturbance in ER homeostasis. The colocalization of phytoplasmas with the accumulated ER-resident proteins suggests an association between ER stress, unfolded protein response (UPR) induction, and phytoplasma infection and colonization, with the ER stress response likely contributing to the host plant's defense mechanisms. Quantitative real-time PCR revealed a negative correlation between ER stress/UPR activation and PPT phytoplasma titer, implying the involvement of UPR in curbing phytoplasma proliferation. Inducing ER stress and activating the UPR pathway effectively decreased phytoplasma titer, while suppressing the ER-resident protein, binding immunoglobulin protein (BiP) increased phytoplasma titer. These results highlight the ER as an intracellular battleground where phytoplasmas exploit host components for survival and multiplication, while host plants deploy defense mechanisms to counteract the invasion. Understanding the intricate interactions between phytoplasmas and plant hosts at the subcellular level, particularly within the ER, provides valuable insights for developing new strategies to control phytoplasma diseases.
Topics: Phytoplasma; Endoplasmic Reticulum Stress; Unfolded Protein Response; Aggression; Endoplasmic Reticulum
PubMed: 37626920
DOI: 10.3390/cells12162110 -
Ageing Research Reviews Jul 2024Aging is a gradual and irreversible natural process. With aging, the body experiences a functional decline, and the effects amplify the vulnerability to a range of... (Review)
Review
Aging is a gradual and irreversible natural process. With aging, the body experiences a functional decline, and the effects amplify the vulnerability to a range of age-related diseases, including neurodegenerative, cardiovascular, and metabolic diseases. Within the aging process, the morphology and function of mitochondria and the endoplasmic reticulum (ER) undergo alterations, particularly in the structure connecting these organelles known as mitochondria-associated membranes (MAMs). MAMs serve as vital intracellular signaling hubs, facilitating communication between the ER and mitochondria when regulating various cellular events, including calcium homeostasis, lipid metabolism, mitochondrial function, and apoptosis. The formation of MAMs is partly dependent on the interaction between the vesicle-associated membrane protein-associated protein-B (VAPB) and protein tyrosine phosphatase-interacting protein-51 (PTPIP51). Accumulating evidence has begun to elucidate the pivotal role of the VAPB-PTPIP51 tether in the initiation and progression of age-related diseases. In this study, we delineate the intricate structure and multifunctional role of the VAPB-PTPIP51 tether and discuss its profound implications in aging-associated diseases. Moreover, we provide a comprehensive overview of potential therapeutic interventions and pharmacological agents targeting the VAPB-PTPIP51-mediated MAMs, thereby offering a glimmer of hope in mitigating aging processes and treating age-related disorders.
Topics: Humans; Aging; Endoplasmic Reticulum; Mitochondria; Animals; Vesicular Transport Proteins; Mitochondrial Proteins; Protein Tyrosine Phosphatases
PubMed: 38719161
DOI: 10.1016/j.arr.2024.102320 -
The Journal of Biological Chemistry Apr 2024The unfolded protein response is a mechanism aiming at restoring endoplasmic reticulum (ER) homeostasis and is likely involved in other adaptive pathways. The unfolded... (Review)
Review
The unfolded protein response is a mechanism aiming at restoring endoplasmic reticulum (ER) homeostasis and is likely involved in other adaptive pathways. The unfolded protein response is transduced by three proteins acting as sensors and triggering downstream signaling pathways. Among them, inositol-requiring enzyme 1 alpha (IRE1α) (referred to as IRE1 hereafter), an endoplasmic reticulum-resident type I transmembrane protein, exerts its function through both kinase and endoribonuclease activities, resulting in both X-box binding protein 1 mRNA splicing and RNA degradation (regulated ire1 dependent decay). An increasing number of studies have reported protein-protein interactions as regulators of these signaling mechanisms, and additionally, driving other noncanonical functions. In this review, we deliver evolutive and structural insights on IRE1 and further describe how this protein interaction network (interactome) regulates IRE1 signaling abilities or mediates other cellular processes through catalytic-independent mechanisms. Moreover, we focus on newly discovered targets of IRE1 kinase activity and discuss potentially novel IRE1 functions based on the nature of the interactome, thereby identifying new fields to explore regarding this protein's biological roles.
Topics: Animals; Humans; Endoplasmic Reticulum; Endoribonucleases; Protein Interaction Maps; Protein Serine-Threonine Kinases; Signal Transduction; Unfolded Protein Response; Evolution, Molecular
PubMed: 38494075
DOI: 10.1016/j.jbc.2024.107169 -
Journal of Experimental & Clinical... Mar 2024A firm link between endoplasmic reticulum (ER) stress and tumors has been wildly reported. Endoplasmic reticulum oxidoreductase 1 alpha (ERO1α), an ER-resident thiol... (Review)
Review
A firm link between endoplasmic reticulum (ER) stress and tumors has been wildly reported. Endoplasmic reticulum oxidoreductase 1 alpha (ERO1α), an ER-resident thiol oxidoreductase, is confirmed to be highly upregulated in various cancer types and associated with a significantly worse prognosis. Of importance, under ER stress, the functional interplay of ERO1α/PDI axis plays a pivotal role to orchestrate proper protein folding and other key processes. Multiple lines of evidence propose ERO1α as an attractive potential target for cancer treatment. However, the unavailability of specific inhibitor for ERO1α, its molecular inter-relatedness with closely related paralog ERO1β and the tightly regulated processes with other members of flavoenzyme family of enzymes, raises several concerns about its clinical translation. Herein, we have provided a detailed description of ERO1α in human cancers and its vulnerability towards the aforementioned concerns. Besides, we have discussed a few key considerations that may improve our understanding about ERO1α in tumors.
Topics: Humans; Clinical Relevance; Endoplasmic Reticulum; Endoplasmic Reticulum Stress; Membrane Glycoproteins; Neoplasms; Oxidation-Reduction; Oxidoreductases
PubMed: 38454454
DOI: 10.1186/s13046-024-02990-4 -
Nature Communications Feb 2024Contact between organelles such as the mitochondria (Mito) and endoplasmic reticulum (ER) is crucial to coordinate vital cellular homeostatic processes. Here we discuss...
Contact between organelles such as the mitochondria (Mito) and endoplasmic reticulum (ER) is crucial to coordinate vital cellular homeostatic processes. Here we discuss recent work showing that Mito-ER proximity is regulated by heterotypic complexes between the F-actin polymerizing protein Diaphanous-1) and the mitochondrial dynamics protein Mitofusin 2, which confers increased susceptibility to ischemia/reperfusion injury.
Topics: Humans; Myocardial Ischemia; Endoplasmic Reticulum; Coronary Artery Disease; Endoplasmic Reticulum Stress; Apoptosis; Myocytes, Cardiac; Formins; GTP Phosphohydrolases; Mitochondrial Proteins
PubMed: 38368414
DOI: 10.1038/s41467-024-45560-0 -
Chemico-biological Interactions Sep 2023Accumulation of the heavy metals molybdenum (Mo) and cadmium (Cd) in the liver can induce organelle damage and inflammation, resulting in hepatotoxicity. The effect of...
Accumulation of the heavy metals molybdenum (Mo) and cadmium (Cd) in the liver can induce organelle damage and inflammation, resulting in hepatotoxicity. The effect of Mo and/or Cd on sheep hepatocytes was investigated by determining the relationship between the mitochondria-associated endoplasmic reticulum membrane (MAM) and NLRP3 inflammasome. Sheep hepatocytes were divided into four groups: the control group, Mo group (600 μM Mo), Cd group (4 μM Cd) and Mo + Cd group (600 μM Mo+4 μM Cd). The results showed that Mo and/or Cd exposure increased the levels of lactate dehydrogenase (LDH) and nitric oxide (NO) in the cell culture supernatant, elevated the levels of intracellular Ca and mitochondrial Ca, downregulated the expression of MAM-related factors (IP3R, GRP75, VDAC1, PERK, ERO1-α, Mfn1, Mfn2, ERP44), shortened the length of the MAM and reduced the formation of the MAM structure, eventually causing MAM dysfunction. Moreover, the expression levels of NLRP3 inflammasome-related factors (NLRP3, Caspase1, IL-1β, IL-6, TNF-α) were also dramatically increased after Mo and Cd exposure, triggering NLRP3 inflammasome production. However, an IP3R inhibitor, 2-APB treatment significantly alleviated these changes. Overall, the data indicate that Mo and Cd coexposure leads to structural disruption and dysfunction of MAM, disrupts cellular Ca homeostasis, and increases NLRP3 inflammasome production in sheep hepatocytes. However, the inhibition of IP3R alleviates NLRP3 inflammasome production induced by Mo and Cd.
Topics: Animals; Sheep; Inflammasomes; NLR Family, Pyrin Domain-Containing 3 Protein; Cadmium; Molybdenum; Hepatocytes; Endoplasmic Reticulum; Mitochondria
PubMed: 37385403
DOI: 10.1016/j.cbi.2023.110617 -
Nature Communications Aug 2023Junctions between the endoplasmic reticulum (ER) and the plasma membrane (PM) are specialized membrane contacts ubiquitous in eukaryotic cells. Concentration of...
Junctions between the endoplasmic reticulum (ER) and the plasma membrane (PM) are specialized membrane contacts ubiquitous in eukaryotic cells. Concentration of intracellular signaling machinery near ER-PM junctions allows these domains to serve critical roles in lipid and Ca signaling and homeostasis. Subcellular compartmentalization of protein kinase A (PKA) signaling also regulates essential cellular functions, however, no specific association between PKA and ER-PM junctional domains is known. Here, we show that in brain neurons type I PKA is directed to Kv2.1 channel-dependent ER-PM junctional domains via SPHKAP, a type I PKA-specific anchoring protein. SPHKAP association with type I PKA regulatory subunit RI and ER-resident VAP proteins results in the concentration of type I PKA between stacked ER cisternae associated with ER-PM junctions. This ER-associated PKA signalosome enables reciprocal regulation between PKA and Ca signaling machinery to support Ca influx and excitation-transcription coupling. These data reveal that neuronal ER-PM junctions support a receptor-independent form of PKA signaling driven by membrane depolarization and intracellular Ca, allowing conversion of information encoded in electrical signals into biochemical changes universally recognized throughout the cell.
Topics: Signal Transduction; Brain; Cell Membrane; Endoplasmic Reticulum; Neurons
PubMed: 37633939
DOI: 10.1038/s41467-023-40930-6 -
Nature Communications Apr 2024Uncontrolled secretion of ECM proteins, such as collagen, can lead to excessive scarring and fibrosis and compromise tissue function. Despite the widespread occurrence...
Uncontrolled secretion of ECM proteins, such as collagen, can lead to excessive scarring and fibrosis and compromise tissue function. Despite the widespread occurrence of fibrotic diseases and scarring, effective therapies are lacking. A promising approach would be to limit the amount of collagen released from hyperactive fibroblasts. We have designed membrane permeant peptide inhibitors that specifically target the primary interface between TANGO1 and cTAGE5, an interaction that is required for collagen export from endoplasmic reticulum exit sites (ERES). Application of the peptide inhibitors leads to reduced TANGO1 and cTAGE5 protein levels and a corresponding inhibition in the secretion of several ECM components, including collagens. Peptide inhibitor treatment in zebrafish results in altered tissue architecture and reduced granulation tissue formation during cutaneous wound healing. The inhibitors reduce secretion of several ECM proteins, including collagens, fibrillin and fibronectin in human dermal fibroblasts and in cells obtained from patients with a generalized fibrotic disease (scleroderma). Taken together, targeted interference of the TANGO1-cTAGE5 binding interface could enable therapeutic modulation of ERES function in ECM hypersecretion, during wound healing and fibrotic processes.
Topics: Humans; Animals; Fibroblasts; Collagen; Wound Healing; Cicatrix; Zebrafish; Skin; Fibrosis; Peptides; Endoplasmic Reticulum; Scleroderma, Systemic; Extracellular Matrix
PubMed: 38658535
DOI: 10.1038/s41467-024-47004-1