The neuroimmune nexus: unraveling the role of the mtDNA-cGAS-STING signal pathway in Alzheimer’s disease

Molecular Neurodegeneration, Journal Year: 2025, Volume and Issue: 20(1)

Published: March 4, 2025

The relationship between Alzheimer's disease (AD) and neuroimmunity has gradually begun to be unveiled. Emerging evidence indicates that cyclic GMP-AMP synthase (cGAS) acts as a cytosolic DNA sensor, recognizing damage-associated molecular patterns (DAMPs), inducing the innate immune response by activating stimulator of interferon genes (STING). Dysregulation this pathway culminates in AD-related neuroinflammation neurodegeneration. A substantial body mitochondria are involved critical pathogenic mechanisms AD, whose damage leads release mitochondrial (mtDNA) into extramitochondrial space. This leaked mtDNA serves DAMP, various pattern recognition receptors defense networks brain, including cGAS-STING pathway, ultimately leading an imbalance homeostasis. Therefore, modulation mtDNA-cGAS-STING restore neuroimmune homeostasis may offer promising prospects for improving AD treatment outcomes. In review, we focus on during stress activation pathway. Additionally, delve research progress further discuss primary directions potential hurdles developing targeted therapeutic drugs, gain deeper understanding pathogenesis provide new approaches its therapy.

Language: Английский

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The pathobiology of neurovascular aging

Neuron, Journal Year: 2025, Volume and Issue: 113(1), P. 49 - 70

Published: Jan. 1, 2025

Language: Английский

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Game changer: Navigating between challenges and hopes in geropharmacology

Advances in pharmacology, Journal Year: 2025, Volume and Issue: unknown

Published: Jan. 1, 2025

Language: Английский

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Unraveling the cGAS-STING pathway in Alzheimer’s disease: A new Frontier in neuroinflammation and therapeutic strategies

Neuroscience, Journal Year: 2025, Volume and Issue: unknown

Published: April 1, 2025

Language: Английский

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Mitochondrial dysfunction in AMI: mechanisms and therapeutic perspectives

Journal of Translational Medicine, Journal Year: 2025, Volume and Issue: 23(1)

Published: April 10, 2025

Acute myocardial infarction (AMI) and the ischemia-reperfusion injury (MI/RI) that typically ensues represent a significant global health burden, accounting for considerable number of deaths disabilities. In context AMI, percutaneous coronary intervention (PCI) is preferred treatment option reducing acute ischemic damage to heart. Despite modernity PCI therapy, pathological cardiomyocytes due MI/RI remains an important target affects long-term prognosis patients. recent years, mitochondrial dysfunction during AMI has been increasingly recognized as critical factor in cardiomyocyte death. Damaged mitochondria play active role formation inflammatory environment by triggering key signaling pathways, including those mediated cyclic GMP-AMP synthase, NOD-like receptors Toll-like receptors. This review emphasizes dual both contributors regulators inflammation. The aim explore complex mechanisms its profound impact on immune dysregulation. Specific interventions mitochondrial-targeted antioxidants, membrane-stabilizing peptides, transplantation therapies have demonstrated efficacy preclinical models.

Language: Английский

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Mitochondria – the CEO of the cell

Journal of Cell Science, Journal Year: 2025, Volume and Issue: 138(9)

Published: May 1, 2025

As we have learned more about mitochondria over the past decades, including their essential cellular roles and how altered mitochondrial biology results in disease, it has become apparent that they are not just powerplants pumping out ATP at whim of cell. Rather, dynamic information energy processors play crucial directing dozens processes behaviors. They provide instructions to enact programs regulate various operations, such as complex metabolic networks, signaling innate immunity, even control cell fate, dictating when cells should divide, differentiate or die. To help current future generations biologists incorporate dynamic, multifaceted nature assimilate modern discoveries into scientific framework, need a 21st century 'rebranding'. In this Opinion article, argue be considered 'Chief Executive Organelle' - CEO

Language: Английский

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Persistent Monocytic Bioenergetic Impairment and Mitochondrial DNA Damage in PASC Patients with Cardiovascular Complications

International Journal of Molecular Sciences, Journal Year: 2025, Volume and Issue: 26(10), P. 4562 - 4562

Published: May 9, 2025

Cardiovascular complications are a hallmark of Post-Acute Sequelae Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) infection (PASC), yet the mechanisms driving persistent cardiac dysfunction remain poorly understood. Emerging evidence implicates mitochondrial in immune cells as key contributor. This study investigated whether CD14++ monocytes from long COVID patients exhibit bioenergetic impairment, DNA (mtDNA) damage, and defective oxidative stress adaptation, which may underlie cardiovascular symptoms PASC. were isolated 14 with (e.g., dyspnea, angina) 10 age-matched controls similar risk profiles. Mitochondrial function was assessed using Seahorse Agilent Analyzer under basal conditions after induction buthionine sulfoximine (BSO). membrane potential measured via Tetramethylrhodamine Ethyl Ester (TMRE) assay, mtDNA integrity qPCR, reactive oxygen species (ROS) dynamics Fluorescence-Activated Cell Sorting (FACS). Parallel experiments exposed healthy to SARS-CoV-2 spike protein evaluate direct viral effects. (n = 14) exhibited profound compared 10). Under induced by (BSO), failed upregulate respiration (9.5 vs. 30.4 pmol/min controls, p 0.0043), showed 65% reduction maximal (p 0.4035, ns) demonstrated 70% loss spare respiratory capacity 0.4143, significantly impaired adaptation BSO challenge (long + BSO: 9.9 control 54 pmol/min, 0.0091). Proton leak, protective mechanism against ROS overproduction, blunted (3-fold 13-fold elevation 0.0294). Paradoxically, reduced accumulation treatment (6% decrease 1.2-fold increase 0.0015) elevated (157 113.7 TMRE fluorescence, 0.0179), remained stable stress. analysis revealed severe depletion (80% reduction, < 0.001) region-specific 75% reductions amplification efficiency for regions C D 0.05), respectively. In contrast, exposure did not recapitulate these defects, preserved respiration, ATP production, capacity, though coupling 0.05). These findings suggest that syndrome arises maladaptive host responses rather than toxicity, characterized failure, genomic instability. identifies critical driver Key defects—bioenergetic damage—correlate clinical like heart failure exercise intolerance. The resistance remodeling physiology. position resilience therapeutic target, strategies including antioxidants, repair agents or metabolic modulators. dissociation between highlights need explore host-directed PASC pathophysiology. work advances our understanding sequelae provides foundation biomarker development targeted interventions mitigate long-term morbidity.

Language: Английский

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Don´t give up on mitochondria as a target for the treatment of diabetes and its complications

World Journal of Diabetes, Journal Year: 2024, Volume and Issue: 15(10), P. 2015 - 2021

Published: Sept. 26, 2024

In this editorial, we discuss an article by Wang et al , focusing on the role of mitochondria in peripheral insulin resistance and secretion. Despite numerous vitro pre-clinical studies supporting involvement mitochondrial dysfunction oxidative stress pathogenesis diabetes its complications, efforts to target for glycemic control using mitochondria-targeted antioxidants have produced inconsistent results. The intricate functionality is summarized underscore challenges it poses as a therapeutic target. While demonstrated improvement function models, results regarding been mixed, no evaluated their hypoglycemic effects diabetic patients. Nonetheless, trials shown promising outcomes ameliorating diabetes-related complications. Here, review some reasons why may not effectively context dysfunction. We also highlight several alternative approaches under development that enhance targeting treatment.

Language: Английский

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Phosphoproteomics highlights complex resource management upon inflammatory stimulation of fibroblasts

bioRxiv (Cold Spring Harbor Laboratory), Journal Year: 2024, Volume and Issue: unknown

Published: Oct. 11, 2024

ABSTRACT The stimulation of cells by inflammatory mediators gives rise to intricate signaling cascades, inducing specific biological functions. role kinase activation for the establishment functions has only scarcely been established. A time-course analysis human fetal fibroblasts stimulated with Interleukin-1β (IL-1β) and/or Dexamethasone (Dex) was conducted using mass spectrometry-based proteomics and phosphoproteomics in conjunction lysolipid oxylipin profiling. IL-1β induced proteome alterations indicated metabolic, transcriptional, translational activation, including marker proteins such as NOS1, THBS1, STING1. induction mitochondrial formation numerous lysolipids an increase beta-oxidation. In addition NF-κB STAT pathways, which are characteristic MAP AKT pathways were found be strongly induced. Six hours after treatment, observed events exhibited a notable decline, nearly returning their initial states 24 hours. It is noteworthy that all these activities also treated Dex alone. Additionally, transient alterations, included otherwise response, MMP3 NFKB2. Activation PIKFYVE apparently dexamethasone but constituted minority total phosphorylation events. Only glucocorticoids, TSC22D3 MAOA, observed. effects on background established verified known inhibitory resulted expression anti-inflammatory oxylipins, hardly affected involving kinases. conclusion, this data demonstrates majority inflammation-associated needs attributed resource stress management rather than effector

Language: Английский

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