Hexokinase dissociation from mitochondria promotes oligomerization of VDAC that facilitates NLRP3 inflammasome assembly and activation

Science Immunology, Journal Year: 2023, Volume and Issue: 8(84)

Published: June 16, 2023

NLRP3 inflammasome activation is a highly regulated process for controlling secretion of the potent inflammatory cytokines IL-1β and IL-18 that are essential during bacterial infection, sterile inflammation, disease, including colitis, diabetes, Alzheimer's atherosclerosis. Diverse stimuli activate inflammasome, unifying upstream signals has been challenging to identify. Here, we report common step in dissociation glycolytic enzyme hexokinase 2 from voltage-dependent anion channel (VDAC) outer membrane mitochondria. Hexokinase VDAC triggers inositol triphosphate receptors, leading release calcium ER, which taken up by This influx into mitochondria leads oligomerization VDAC, known form macromolecule-sized pore membranes allows proteins mitochondrial DNA (mtDNA), often associated with apoptosis respectively, exit We observe oligomers aggregate initial assembly multiprotein oligomeric complex. also find mtDNA necessary association oligomers. These data, together other recent work, help paint more complete picture pathway activation.

Language: Английский

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Targeting pyroptosis with nanoparticles to alleviate neuroinflammatory for preventing secondary damage following traumatic brain injury

Science Advances, Journal Year: 2024, Volume and Issue: 10(2)

Published: Jan. 10, 2024

Posttraumatic neuroinflammation is a key driver of secondary injury after traumatic brain (TBI). Pyroptosis, proinflammatory form programmed cell death, considerably activates strong and amplifies the inflammatory response by releasing contents. Therefore, treatments targeting pyroptosis may have beneficial effects on treatment damage TBI. Here, cysteine-alanine-glutamine-lysine peptide-modified β-lactoglobulin (β-LG) nanoparticle was constructed to deliver disulfiram (DSF), C-β-LG/DSF, inhibit decrease neuroinflammation, thereby preventing TBI-induced injury. In post-TBI mice model, C-β-LG/DSF selectively targets injured brain, increases DSF accumulation, extends time systemic circulation DSF. can alleviate edema response, injury, promote learning, improve memory recovery in trauma. this study likely provided potential approach for reducing spread

Language: Английский

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Microplastics exposure promotes the proliferation of skin cancer cells but inhibits the growth of normal skin cells by regulating the inflammatory process

Ecotoxicology and Environmental Safety, Journal Year: 2023, Volume and Issue: 267, P. 115636 - 115636

Published: Nov. 1, 2023

Cutaneous squamous cell carcinoma (CSCC) is one of the most common malignant tumors skin, occurring primarily in elderly population. CSCC second nonmelanoma skin malignancy humans. The development cutaneous closely linked to environmental factors. Microplastics, as a new pollutant, are currently being intensively studied for their potential health effects. However, effect microplastics on cancer not yet known and an important scientific question that needs be addressed. To this end, current study, two lines (SCL-1 A431) were utilized investigate effects cancer, behavior experiments showed internalized into line time- dose-dependent manner. Further promoted proliferation cells by MTT, flow cytometry, laser confocal microscopy, Western blotting other experimental techniques. Mechanistic studies could lead increased mitochondrial ROS cells, which turn caused change membrane potential, thus opening mPTP, release mt-DNA from mitochondria cytoplasm, activating NLRP3 ultimately causing proliferation. We further evaluated HaCaT normal model damage through NLRP3-mediated inflammation scorch death. study suggests microplastics, contaminant, may promote tumor while skin.

Language: Английский

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IQGAP1 promotes mitochondrial damage and activation of the mtDNA sensor cGAS-STING pathway to induce endothelial cell pyroptosis leading to atherosclerosis

International Immunopharmacology, Journal Year: 2023, Volume and Issue: 123, P. 110795 - 110795

Published: Aug. 17, 2023

Language: Английский

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Role of NLRP3 inflammasome-mediated neuronal pyroptosis and neuroinflammation in neurodegenerative diseases

Inflammation Research, Journal Year: 2023, Volume and Issue: 72(9), P. 1839 - 1859

Published: Sept. 1, 2023

Language: Английский

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Restoring the infected powerhouse: Mitochondrial quality control in sepsis

Redox Biology, Journal Year: 2023, Volume and Issue: 68, P. 102968 - 102968

Published: Nov. 23, 2023

Sepsis is a dysregulated host response to an infection, characterized by organ failure. The pathophysiology complex and incompletely understood, but mitochondria appear play key role in the cascade of events that culminate multiple failure potentially death. In shaping immune responses, fulfil dual roles: they not only supply energy metabolic intermediates crucial for cell activation function also influence inflammatory death pathways. Importantly, mitochondrial dysfunction has impact, compromising both system efficiency stability end organs. Dysfunctional contribute development hyperinflammatory state loss cellular homeostasis, resulting poor clinical outcomes. Already early sepsis, signs are apparent consequently, strategies optimize sepsis should prevent occurrence dysfunction, cover repair sustained damage. Here, we discuss quality control (mtQC) pathogenesis exemplify how mtQC could serve as therapeutic target overcome dysfunction. Hence, replacing or repairing dysfunctional may recovery sepsis. Mitochondrial biogenesis process results formation new critical maintaining pool healthy mitochondria. However, exacerbated during can result accumulation structurally aberrant fail restore bioenergetics, produce excess reactive oxygen species (ROS) exacerbate disease course. Conversely, enhancing mitophagy protect against damage limiting release mitochondrial-derived damage-associated molecules (DAMPs). Furthermore, promoting facilitate growth blocking replication damaged allow post through enabling mitophagy-coupled biogenesis. remaining provide undamaged scaffold reproduce functional kinetics specifically mitophagy, optimal timing intervention remain poorly understood. This review emphasizes importance integrating induction with mechanisms undesired effects associated solely

Language: Английский

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IFNγ causes mitochondrial dysfunction and oxidative stress in myositis

Nature Communications, Journal Year: 2024, Volume and Issue: 15(1)

Published: June 26, 2024

Abstract Idiopathic inflammatory myopathies (IIMs) are severe autoimmune diseases with poorly understood pathogenesis and unmet medical needs. Here, we examine the role of interferon γ (IFNγ) using NOD female mice deficient in inducible T cell co-stimulator ( Icos ), which have previously been shown to develop spontaneous IFNγ-driven myositis mimicking human disease. Using muscle proteomic spatial transcriptomic analyses reveal profound myofiber metabolic dysregulation these mice. In addition, report mitochondrial abnormalities oxidative stress diseased Supporting a pathogenic for stress, treatment reactive oxygen species (ROS) buffer compound alleviated myositis, preserved ultrastructure respiration, reduced inflammation. Mitochondrial anomalies were diminished following anti-IFNγ treatment. Further analysis IIMs patients myoblast vitro studies supported link between IFNγ dysfunction observed These results suggest that dysfunction, ROS inflammation interconnected self-maintenance loop, opening perspectives mitochondria therapy and/or targeting drugs myositis.

Language: Английский

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Extracellular vesicles meet mitochondria: Potential roles in regenerative medicine

Pharmacological Research, Journal Year: 2024, Volume and Issue: 206, P. 107307 - 107307

Published: July 14, 2024

Extracellular vesicles (EVs), secreted by most cells, act as natural cell-derived carriers for delivering proteins, nucleic acids, and organelles between cells. Mitochondria are highly dynamic responsible energy production cellular physiological processes. Recent evidence has highlighted the pivotal role of EVs in intercellular mitochondrial content transfer, including DNA (mtDNA), intact mitochondria. Intriguingly, mitochondria crucial mediators release, suggesting an interplay their potential implications physiology pathology. However, this expanding field, much remains unknown regarding function mechanism crosstalk transport EVs. Herein, we shed light on pathological functions mitochondria, mechanisms underlying interactions, delivery mitochondria-rich EVs, clinical applications regenerative medicine.

Language: Английский

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HCAR2 Modulates the Crosstalk between Mammary Epithelial Cells and Macrophages to Mitigate Staphylococcus aureus Infection in the Mouse Mammary Gland

Advanced Science, Journal Year: 2025, Volume and Issue: unknown

Published: Jan. 10, 2025

Abstract Staphylococcus aureus ( S. ) is a major zoonotic pathogen, with mammary gland infections contributing to mastitis, condition that poses significant health risks lactating women and adversely affects the dairy industry. Therefore, understanding immune mechanisms underlying caused by essential for developing targeted therapeutic strategies against mastitis. This study identified hydroxycarboxylic acid receptor 2 (HCAR2) as potential regulator of infection in glands. It demonstrated HCAR2 deficiency exacerbates inflammatory response disrupts blood‐milk barrier during infection, NLRP3 inflammasome‐mediated pyroptosis playing central role. Activation HCAR2, on other hand, suppressed CMPK2 expression, thereby mitigating mitochondrial damage mouse epithelial cells (mMECs) induced . Additionally, DNA (mtDNA) released from ‐infected mMECs activates cGAS/STING signaling pathway macrophages, impairing their bactericidal activity. In conclusion, this highlights critical role provides theoretical basis identifying targets such infections.

Language: Английский

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Mitochondrial Damage-Associated Molecular Patterns Content in Extracellular Vesicles Promotes Early Inflammation in Neurodegenerative Disorders

Cells, Journal Year: 2022, Volume and Issue: 11(15), P. 2364 - 2364

Published: Aug. 1, 2022

Neuroinflammation is a common hallmark in different neurodegenerative conditions that share neuronal dysfunction and progressive loss of selectively vulnerable brain cell population. Alongside ageing genetics, inflammation, oxidative stress mitochondrial are considered key risk factors. Microglia immune sentinels the central nervous system capable initiating an innate adaptive response. Nevertheless, pathological mechanisms underlying initiation spread inflammation still poorly described. Recently, new mechanism intercellular signalling mediated by small extracellular vesicles (EVs) has been identified. EVs nanosized particles (30–150 nm) with bilipid membrane carries cell-specific bioactive cargos participate physiological or processes. Damage-associated molecular patterns (DAMPs) cellular components recognised receptors microglia, inducing aggravating neuroinflammation disorders. Diverse evidence links mitochondrial-DAMPs (mtDAMPs) such as DNA, transcription factor A (TFAM) cardiolipin, among others. Mitochondrial-derived (MDVs) subtype produced after mild damage to mitochondria and, upon fusion multivesicular bodies released space. MDVs particularly enriched mtDAMPs which can induce response release pro-inflammatory cytokines. Importantly, growing supports association between dysfunction, EV inflammation. Here, we describe role vesicles-associated mtDAMPS activators contributing

Language: Английский

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