Mitochondria-associated programmed cell death as a therapeutic target for age-related disease

Experimental & Molecular Medicine, Journal Year: 2023, Volume and Issue: 55(8), P. 1595 - 1619

Published: Aug. 23, 2023

Abstract Mitochondria, ubiquitous double-membrane-bound organelles, regulate energy production, support cellular activities, harbor metabolic pathways, and, paradoxically, mediate cell fate. Evidence has shown mitochondria as points of convergence for diverse death-inducing pathways that trigger the various mechanisms underlying apoptotic and nonapoptotic programmed death. Thus, dysfunctional eventually lead or contribute to age-related diseases, such neurodegenerative, cardiovascular diseases. mitochondrion-associated death-based treatments show great therapeutic potential, providing novel insights in clinical trials. This review discusses mitochondrial quality control networks with activity triggered by stimuli maintain homeostasis via mitohormesis, unfolded protein response, mitophagy. The also presents details on forms mitochondria-associated death, including apoptosis, necroptosis, ferroptosis, pyroptosis, parthanatos, paraptosis, highlights their involvement disease pathogenesis, collectively suggesting directions further research.

Language: Английский

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Polydopamine Nanoparticles Targeting Ferroptosis Mitigate Intervertebral Disc Degeneration Via Reactive Oxygen Species Depletion, Iron Ions Chelation, and GPX4 Ubiquitination Suppression

Advanced Science, Journal Year: 2023, Volume and Issue: 10(13)

Published: March 23, 2023

Intervertebral disc degeneration (IVDD)-induced lower back pain (LBP) is a common problem worldwide. The underlying mechanism partially accredited to ferroptosis, based on sequencing analyses of IVDD patients from the gene expression omnibus (GEO) databases. In this study, it shown that polydopamine nanoparticles (PDA NPs) inhibit oxidative stress-induced ferroptosis in nucleus pulposus (NP) cells vitro. PDA NPs scavenge reactive oxygen species (ROS), chelate Fe

Language: Английский

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cGAS-STING, inflammasomes and pyroptosis: an overview of crosstalk mechanism of activation and regulation

Cell Communication and Signaling, Journal Year: 2024, Volume and Issue: 22(1)

Published: Jan. 9, 2024

Abstract Background Intracellular DNA-sensing pathway cGAS-STING, inflammasomes and pyroptosis act as critical natural immune signaling axes for microbial infection, chronic inflammation, cancer progression organ degeneration, but the mechanism regulation of crosstalk network remain unclear. Main body abstract Cellular stress disrupts mitochondrial homeostasis, facilitates opening permeability transition pore leakage DNA to cell membrane, triggers inflammatory responses by activating cGAS-STING signaling, subsequently induces activation onset pyroptosis. Meanwhile, inflammasome-associated protein caspase-1, Gasdermin D, CARD domain ASC potassium channel are involved in regulating pathway. Importantly, this has a cascade amplification effect that exacerbates immuno-inflammatory response, worsening pathological process autoimmune diseases. Given importance innate immunity, it is emerging new avenue explore mechanisms multiple disease pathogenesis. Therefore, efforts define strategies selectively modulate different settings have been or ongoing. In review, we will describe how mechanistic understanding driving possible therapeutics targeting network, focusing on interacting regulatory proteins, pathways, hub between inflammasomes, Short conclusion This review aims provide insight into roles pyroptosis, highlight some promising directions future research intervention.

Language: Английский

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Nucleus pulposus cells regulate macrophages in degenerated intervertebral discs via the integrated stress response-mediated CCL2/7-CCR2 signaling pathway

Experimental & Molecular Medicine, Journal Year: 2024, Volume and Issue: 56(2), P. 408 - 421

Published: Feb. 5, 2024

Abstract Lower back pain (LBP), which is a primary cause of disability, largely attributed to intervertebral disc degeneration (IDD). Macrophages (MΦs) in degenerated discs (IVDs) form chronic inflammatory microenvironment, but how MΦs are recruited degenerative segments and transform into proinflammatory phenotype remains unclear. We evaluated chemokine expression nucleus pulposus cells (NPCs) clarify the role NPCs establishment an microenvironment IDD explored mechanisms. found that production C-C motif ligand 2 (CCL2) 7 (CCL7) was significantly increased under conditions, blocking CCL2/7 their receptor, receptor type 2(CCR2), inhibited inductive effects on MΦ infiltration polarization. Moreover, activation integrated stress response (ISR) obvious IDD, ISR inhibition reduced NPCs. Further investigation revealed activating Transcription Factor 3 (ATF3) responded activation, ChIP-qPCR verified DNA-binding activity ATF3 promoters. In addition, we Toll-like 4 (TLR4) modulated TLR4 regulated accumulation mitochondrial reactive oxygen species (mtROS) double-stranded RNA (dsRNA). Downregulating level mtROS amount dsRNA activation. Deactivating or release alleviated inflammation progression vivo. were CCR2-knockout mice. conclusion, this study highlights critical TLR4/mtROS/dsRNA axis-mediated provides promising therapeutic strategies for discogenic LBP.

Language: Английский

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Oxidized mitochondrial DNA activates the cGAS-STING pathway in the neuronal intrinsic immune system after brain ischemia-reperfusion injury

Neurotherapeutics, Journal Year: 2024, Volume and Issue: 21(4), P. e00368 - e00368

Published: April 30, 2024

In the context of stroke and revascularization therapy, brain ischemia-reperfusion injury is a significant challenge that leads to oxidative stress inflammation. Central cell's intrinsic immunity cGAS-STING pathway, which typically activated by unusual DNA structures. The involvement oxidized mitochondrial (ox-mtDNA)-an byproduct-in this type neurological damage has not been fully explored. This study among first examine effect ox-mtDNA on innate neurons following injury. Using rat model transient middle cerebral artery occlusion cellular oxygen-glucose deprivation/reoxygenation, we have discovered activates pathway in neurons. Importantly, pharmacologically limiting release into cytoplasm reduces inflammation improves functions. Our findings suggest targeting may be valuable strategy attenuate therapy for acute ischemic stroke.

Language: Английский

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Mitophagy and cGAS–STING crosstalk in neuroinflammation

Acta Pharmaceutica Sinica B, Journal Year: 2024, Volume and Issue: 14(8), P. 3327 - 3361

Published: May 13, 2024

Mitophagy, essential for mitochondrial health, selectively degrades damaged mitochondria. It is intricately linked to the cGAS–STING pathway, crucial innate immunity. This pathway responds DNA and associated with cellular stress. Our review explores molecular details regulatory mechanisms of mitophagy pathway. We critically evaluated literature demonstrating how dysfunctional leads neuroinflammatory conditions, primarily through accumulation mitochondria, activating activation prompts production proinflammatory cytokines, exacerbating neuroinflammation. emphasizes interaction between Effective might suppress offering protection against Conversely, impaired may activate potentially leading chronic Additionally, we explored this influences neurodegenerative disorders, suggesting a common mechanism in such diseases. In conclusion, there need additional targeted research unravel complexities mitophagy–cGAS–STING interactions their role neurodegeneration. highlights potential therapies targeting these pathways, which could lead new treatments conditions. synthesis enhances our understanding foundations neuroinflammation opens therapeutic avenues disease research.

Language: Английский

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Mitochondrial DNA leakage: underlying mechanisms and therapeutic implications in neurological disorders

Journal of Neuroinflammation, Journal Year: 2025, Volume and Issue: 22(1)

Published: Feb. 7, 2025

Mitochondrial dysfunction is a pivotal instigator of neuroinflammation, with mitochondrial DNA (mtDNA) leakage as critical intermediary. This review delineates the intricate pathways leading to mtDNA release, which include membrane permeabilization, vesicular trafficking, disruption homeostatic regulation, and abnormalities in dynamics. The escaped activates cytosolic sensors, especially cyclic gmp-amp synthase (cGAS) signalling inflammasome, initiating neuroinflammatory cascades via pathways, exacerbating spectrum neurological pathologies. therapeutic promise targeting discussed detail, underscoring necessity for multifaceted strategy that encompasses preservation homeostasis, prevention leakage, reestablishment dynamics, inhibition activation sensors. Advancing our understanding complex interplay between neuroinflammation imperative developing precision interventions disorders.

Language: Английский

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Ferroptosis and pyroptosis are connected through autophagy: a new perspective of overcoming drug resistance

Molecular Cancer, Journal Year: 2025, Volume and Issue: 24(1)

Published: Jan. 17, 2025

Drug resistance is a common challenge in clinical tumor treatment. A reduction drug sensitivity of cells often accompanied by an increase autophagy levels, leading to autophagy-related resistance. The effectiveness combining chemotherapy drugs with inducers/inhibitors has been widely confirmed, but the mechanisms are still unclear. Ferroptosis and pyroptosis can be affected various types autophagy. Therefore, ferroptosis have crosstalk via autophagy, potentially switch cell death under certain conditions. As two forms inflammatory programmed death, different effects on inflammation, cGAS-STING signaling pathway also involved. it plays important role progression some chronic diseases. This review discusses relationship between pyroptosis, attempts uncover reasons behind evasion nature

Language: Английский

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Increased TSPO alleviates neuropathic pain by preventing pyroptosis via the AMPK-PGC-1α pathway

The Journal of Headache and Pain, Journal Year: 2025, Volume and Issue: 26(1)

Published: Jan. 27, 2025

Neuropathic pain poses a significant clinical challenge, largely due to the incomplete understanding of its molecular mechanisms, particularly role mitochondrial dysfunction. Bioinformatics analysis revealed that pyroptosis and inflammatory responses induced by spared nerve injury (SNI) in spinal dorsal horn play critical initiation persistence neuropathic pain. Among factors involved, TSPO (translocator protein) emerged as key regulator. Our experimental findings showed expression was upregulated during pain, accompanied dysfunction, specifically manifested impaired biogenesis, disrupted dynamics (including insufficient biogenesis fusion-related proteins, well significantly increased fission-related proteins), activation pyroptosis. Pharmacological upregulation TSPO, but not downregulation, effectively alleviated SNI-induced hypersensitivity, improving function reducing Immunofluorescence staining confirmed primarily localized astrocytes, mirrored protective effects on health prevention. PCR array suggested strong association between regulation pathway AMPK-PGC-1α. Notably, inhibition AMPK-PGC-1α abolished balance suppression. Furthermore, Mendelian randomization GWAS data indicated linked relief. Through drug screening, docking, behavioral assays, we identified zopiclone promising TSPO-targeting for treatment. In summary, this study enhances our interplay health, highlighting potential therapeutic target management.

Language: Английский

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Esketamine alleviates postoperative cognitive decline via stimulator of interferon genes/ TANK‐binding kinase 1 signaling pathway in aged rats

Brain Research Bulletin, Journal Year: 2022, Volume and Issue: 187, P. 169 - 180

Published: July 14, 2022

Language: Английский

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