Mitochondrial DNA Release in Innate Immune Signaling

Annual Review of Biochemistry, Journal Year: 2023, Volume and Issue: 92(1), P. 299 - 332

Published: March 31, 2023

According to the endosymbiotic theory, most of DNA original bacterial endosymbiont has been lost or transferred nucleus, leaving a much smaller (∼16 kb in mammals), circular molecule that is present-day mitochondrial (mtDNA). The ability mtDNA escape mitochondria and integrate into nuclear genome was discovered budding yeast, along with genes regulate this process. Mitochondria have emerged as key regulators innate immunity, it now recognized released cytoplasm, outside cell, circulation activates multiple immune signaling pathways. Here, we first review mechanisms through which including several inducible pores defective mitophagy autophagy. Next, cover how different forms activate specific nucleic acid sensors inflammasomes. Finally, discuss intracellular extracellular release, circulating cell-free promotes systemic inflammation, are implicated human diseases, viral infections, senescence aging.

Language: Английский

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Mitochondria-derived cell-to-cell communication

Cell Reports, Journal Year: 2023, Volume and Issue: 42(7), P. 112728 - 112728

Published: July 1, 2023

In addition to their intracellular mobility, mitochondria and components can exist outside the cells from which they originate. As a result, are capable of acting on non-parental distant mediate intercellular communication in physiological conditions variety pathologies. It has recently been demonstrated that this horizontal transfer governs wide range biological processes, such as tissue homeostasis, rescue injured recipient cells, tumorigenesis. addition, due mitochondria's bacterial ancestry, be recognized damage-associated molecular patterns (DAMPs) by immune leading inflammation. Here, we provide an overview most current significant findings concerning different structures extracellular by-products functions pathological context. This account illustrates ongoing expansion our understanding role mammalian organisms.

Language: Английский

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Current understanding of the cGAS-STING signaling pathway: Structure, regulatory mechanisms, and related diseases

动物学研究, Journal Year: 2023, Volume and Issue: 44(1), P. 183 - 218

Published: Jan. 1, 2023

The innate immune system protects the host from external pathogens and internal damage in various ways. cGAS-STING signaling pathway, comprised of cyclic GMP-AMP synthase (cGAS), stimulator interferon genes (STING), downstream adaptors, plays an essential role protective defense against microbial DNA damaged-associated is responsible for immune-related diseases. After binding with DNA, cytosolic cGAS undergoes conformational change DNA-linked liquid-liquid phase separation to produce 2'3'-cGAMP activation endoplasmic reticulum (ER)-localized STING. However, further studies revealed that predominantly expressed nucleus strictly tethered chromatin prevent nuclear functions differently cytosolic-localized cGAS. Detailed delineation this including its structure, signaling, regulatory mechanisms, great significance fully understand diversity will be benefit treatment inflammatory diseases cancer. Here, we review recent progress on above-mentioned perspectives pathway discuss new avenues study.

Language: Английский

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Vascular “Long COVID”: A New Vessel Disease?

Angiology, Journal Year: 2023, Volume and Issue: 75(1), P. 8 - 14

Published: Jan. 18, 2023

Vascular sequelae following (SARS-CoV-2 coronavirus disease) (COVID)-19 infection are considered as “Long Covid (LC)” disease, when occurring 12 weeks after the original infection. The paucity of specific data can be obviated by translating pathophysiological elements from Severe Acute Respiratory Syndrome-Corona Virus (SARS-CoV-2) (In a microcirculatory system, first “endotheliitis,” is often followed production “Neutrophil Extracellular Trap,” and evolve into more complex leukocytoklastic-like hyperimmune vasculitis. In medium/large-sized vessels, this corresponds to endothelial dysfunction, leading an accelerated progression pre-existing atherosclerotic plaques through increased deposition platelets, circulating inflammatory cells proteins. Associated dysregulated immune pro-coagulant conditions directly cause thrombo-embolic arterial or venous complications. order implement appropriate treatment, physicians need consider vascular pathologies observed SARS-Cov-2 infections possible “LC” disease.

Language: Английский

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Mitochondrial DNA damage triggers spread of Parkinson’s disease-like pathology

Molecular Psychiatry, Journal Year: 2023, Volume and Issue: 28(11), P. 4902 - 4914

Published: Oct. 2, 2023

Abstract In the field of neurodegenerative diseases, especially sporadic Parkinson’s disease (sPD) with dementia (sPDD), question how starts and spreads in brain remains central. While prion-like proteins have been designated as a culprit, recent studies suggest involvement additional factors. We found that oxidative stress, damaged DNA binding, cytosolic sensing, Toll-Like Receptor (TLR)4/9 activation pathways are strongly associated sPDD transcriptome, which has dysregulated type I Interferon (IFN) signaling. sPD patients, we confirmed deletions mitochondrial (mt)DNA medial frontal gyrus, suggesting potential role mtDNA pathophysiology. To explore its contribution to pathology, used spontaneous models caused by deletion IFN signaling ( Ifnb –/– / Ifnar mice). lack neuronal IFNβ/IFNAR leads oxidization, mutation, mtDNA, is subsequently released outside neurons. Injecting into mouse induced PDD-like behavioral symptoms, including neuropsychiatric, motor, cognitive impairments. Furthermore, it neurodegeneration regions distant from injection site, triggers spread PDD characteristics an “infectious-like” manner. also discovered mechanism through causes pathology healthy neurons independent Cyclic GMP-AMP synthase IFNβ/IFNAR, but rather involves dual TLR9/4 pathways, resulting increased stress cell death, respectively. Our proteomic analysis extracellular vesicles containing identified TLR4 activator, Ribosomal Protein S3 key protein involved recognizing extruding mtDNA. These findings might shed light on new molecular initiates PD-like disease, potentially opening avenues for therapeutic interventions or monitoring.

Language: Английский

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Mitochondria Dysfunction and Neuroinflammation in Neurodegeneration: Who Comes First?

Antioxidants, Journal Year: 2024, Volume and Issue: 13(2), P. 240 - 240

Published: Feb. 16, 2024

Neurodegenerative diseases (NDs) encompass an assorted array of disorders such as Alzheimer's disease, Parkinson's and amyotrophic lateral sclerosis, each characterised by distinct clinical manifestations underlying pathological mechanisms. While some cases have a genetic basis, many NDs occur sporadically. Despite their differences, these commonly feature chronic neuroinflammation hallmark. Consensus has recently been reached on the possibility that mitochondria dysfunction protein aggregation can mutually contribute to activation neuroinflammatory response thus onset progression disorders. In present review, we discuss contribution aetiology NDs, highlighting new potential therapeutic targets be identified tackle neurodegenerative processes alleviate pathologies.

Language: Английский

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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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Mitochondrial DNA in NLRP3 inflammasome activation

International Immunopharmacology, Journal Year: 2022, Volume and Issue: 108, P. 108719 - 108719

Published: March 26, 2022

Language: Английский

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Neurodegeneration and Neuroinflammation in Parkinson’s Disease: a Self-Sustained Loop

Current Neurology and Neuroscience Reports, Journal Year: 2022, Volume and Issue: 22(8), P. 427 - 440

Published: June 8, 2022

Abstract Purpose of Review Neuroinflammation plays a significant role in Parkinson’s disease (PD) etiology along with mitochondrial dysfunction and impaired proteostasis. In this context, mechanisms related to immune response can act as modifiers at different steps the neurodegenerative process justify growing interest anti-inflammatory agents potential disease-modifying treatments PD. The discovery inherited gene mutations PD has allowed researchers develop cellular animal models study underlying biology, but original cause neuroinflammation is still debated date. Recent Findings Cell autonomous alterations neuronal cells, including damage protein aggregation, could play role, recent findings also highlighted importance intercellular communication both local systemic level. This given rise debate about non-neuronal cells reignited intense research into gut-brain axis other interactions development disease. Whatever trigger PD, what appears quite clear that aberrant activation glial components system creates vicious circle which neurodegeneration nourish each other. Summary review, we will provide an up-to-date summary main those induced by environmental factors (e.g. gut microbiome) genetic background affected patients. Starting from lesson provided familial forms discuss pathophysiological linked inflammation idiopathic forms. Finally, comment on clinical translatability immunobiomarkers identified patient cohorts update current therapeutic strategies aimed overcoming or preventing

Language: Английский

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Mitochondrial VDAC1: A Potential Therapeutic Target of Inflammation-Related Diseases and Clinical Opportunities

Cells, Journal Year: 2022, Volume and Issue: 11(19), P. 3174 - 3174

Published: Oct. 10, 2022

The multifunctional protein, voltage-dependent anion channel 1 (VDAC1), is located on the mitochondrial outer membrane. It a pivotal protein that maintains function to power cellular bioactivities via energy generation. VDAC1 involved in regulating production, oxidase stress, Ca2+ transportation, substance metabolism, apoptosis, autophagy (mitophagy), and many other functions. malfunction associated with disorders affect inflammatory responses, resulting an up-regulation of body's defensive response stress stimulation. Overresponses inflammation may cause chronic diseases. Mitochondrial DNA (mtDNA) acts as danger signal can further trigger native immune system activities after its secretion. mediates release mtDNA into cytoplasm enhance cytokine levels by activating responses. regulates lipid metabolism mitophagy, which are inflammation-related disease pathogenesis. Many scientists have suggested approaches deal overresponse issues specific targeting therapies. Due broad functionality VDAC1, it become useful target for therapy mechanisms role require exploration. We comprehensively systematically summarized response, hope our research will lead novel therapeutic strategies order treat disorders.

Language: Английский

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