P2X7 Receptor and Purinergic Signaling: Orchestrating Mitochondrial Dysfunction in Neurodegenerative Diseases

Zelentsova, Alexsandra S.; Deykin, Alexey V.; Солдатов, Владислав О.; Ulezko, Anastasia A.; Borisova, Alina Y.; Belyaeva, Veronika S.; Skorkina, M. Yu.; Angelova, Plamena R.

doi:10.1523/eneuro.0092-22.2022

Cited by 15 publications

(4 citation statements)

References 260 publications

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“…Hypoxia increases the baseline ROS levels in glioma cells, but down-regulates ROS generation of that exposed to TMZ Mitochondria are one of the main organelles to produce ROS in cells (Zelentsova et al, 2022). In order to analyze the effects of hypoxia on ROS generation in glioma cells, the H2DCF-DA method was used to detect intracellular ROS levels.…”

Section: Hypoxia Induces the Resistance Of Glioma Cells To Tmzmentioning

confidence: 99%

Hypoxia promotes temozolomide resistance in glioblastoma cells via ROS- mediated up-regulation of TRPM2

Zhao,

peng,

zhu

et al. 2024

Preprint

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Background: Hypoxia, an essential feature of gliomas, is thought to promote chemo-resistance by regulating reactive oxygen species (ROS) levels. Transient receptor potential melastatin 2 (TRPM2) is one of the ion transport proteins and is involved in the regulation of oxidative stress. However, relationship between ROS and TRPM2 expression in hypoxia-induced temozolomide (TMZ) resistance of glioblastoma cells remains unclear. Methods: U87MG cells were cultured with different concentrations of TMZ for the indicated times under normoxia (21% O2) or hypoxia (2.5% O2). Cell viability was detected with WST-1 test and observed by a neurite outgrowth assay. The intracellular ROS scavenging activity was detected according to the H2DCF-DA method. The cells were also treated with the scavenger of ROS NAC and the inhibitor of TRPM2 2-APB. Impaired mitochondrial membrane potential (ΔΨm) and intensity of intracellular Ca2+ were measured under fluorescence microscope. Online database was used to assess the relationship between MGMT and TRPM2 expression level. Western blot was used to analyze the protein levels of TRPM2, MGMT, MSH3 and APNG. Results: Compared with the normoxia group, hypoxia significantly promoted glioma cells survival after treatment by TMZ (200µM) for 24 h or 48 h, accompanied with reduction of mitochondrial dysfunction and intracellular ROS. However, the baseline levels of ROS were mildly increased under hypoxia, which had no impact on mitochondrial function in glioma cells. Additional, TRPM2 expression was obviously increased under hypoxia and inhibited by NAC in glioma cells. We found that the expression levels of TRPM2 were positively correlated with MGMT both in online database (rho=0.165, P < 0.05) and GBM cancer tissues (r=0.9302, P < 0.05). Over-expression of TRPM2 participated in the up-regulation of APNG and MGMT, but down-regulation of MSH3 in glioma cells under hypoxia. Our findings also demonstrated that the treatment group during NAC or 2-APB add-on could significantly attenuate calcium influx, followed by increasing mitochondrial dysfunction and cytotoxicity in glioma cells, in comparison with TMZ alone. Conclusion: The hypoxia-induced up-regulation of baseline ROS levels contributes to the decrease in the sensitivity of glioma cells to TMZ via promoting demethylation and inhibiting DNA mismatch repair. Moreover, TRPM2-mediated Ca2+ influx attenuates mitochondria dysfunction and then protects glioma cells against TMZ damage. TRPM2 may be a potential target in adjuvant treatment with TMZ for glioblastoma multiforme (GBM) patients.

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Section: Hypoxia Induces the Resistance Of Glioma Cells To Tmzmentioning

confidence: 99%

Hypoxia promotes temozolomide resistance in glioblastoma cells via ROS- mediated up-regulation of TRPM2

Zhao,

peng,

zhu

et al. 2024

Preprint

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“…Hence, reduced purinergic receptor function can trigger mitochondrial dysfunction, disrupting the oxidative phosphorylation process and causing oxidative burst, degranulation, and phagocytosis [28]. Additionally, this dysregulation can alter the levels of key second messengers like Ca 2+ ions and reactive oxygen species, ultimately contributing to the development of myopathy and/or neurodegenerative disorders [29][30][31][32].…”

Section: Introductionmentioning

confidence: 99%

Next Generation Sequencing and Electromyography Reveal the Involvement of the P2RX6 Gene in Myopathy

Vinci,

Vitello,

Greco

et al. 2024

CIMB

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Ion channelopathies result from impaired ion channel protein function, due to mutations affecting ion transport across cell membranes. Over 40 diseases, including neuropathy, pain, migraine, epilepsy, and ataxia, are associated with ion channelopathies, impacting electrically excitable tissues and significantly affecting skeletal muscle. Gene mutations affecting transmembrane ionic flow are strongly linked to skeletal muscle disorders, particularly myopathies, disrupting muscle excitability and contraction. Electromyography (EMG) analysis performed on a patient who complained of weakness and fatigue revealed the presence of primary muscular damage, suggesting an early-stage myopathy. Whole exome sequencing (WES) did not detect potentially causative variants in known myopathy-associated genes but revealed a novel homozygous deletion of the P2RX6 gene likely disrupting protein function. The P2RX6 gene, predominantly expressed in skeletal muscle, is an ATP-gated ion channel receptor belonging to the purinergic receptors (P2RX) family. In addition, STRING pathways suggested a correlation with more proteins having a plausible role in myopathy. No previous studies have reported the implication of this gene in myopathy. Further studies are needed on patients with a defective ion channel pathway, and the use of in vitro functional assays in suppressing P2RX6 gene expression will be required to validate its functional role.

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“…4,5 Increasing evidence suggests that the release of reactive oxygen species (ROS), interleukin-6 (IL-6), tumor necrosis factoralpha (TNF-α), interferon-γ (IFN-γ), and other inflammatory factors during inflammation not only regulates the inflammatory process of CNS diseases but also affects the electrophysiological properties of neurons, astrocyte membranes and mitochondrial membranes, initiating the mitochondrial apoptosis pathway and exacerbating neuronal apoptosis and necrosis, leading to secondary brain damage. [6][7][8] Toll-like receptors (TLRs) are the first line of defense against invading pathogens in the host. 9 Toll-like receptor 4 (TLR4) is an important member of the TLR family, and is the main receptor for lipopolysaccharide (LPS) outside the cell wall of gram-negative bacteria.…”

Section: Introductionmentioning

confidence: 99%

“…Inflammation is a normal response of living tissue to stimuli, and the activation and proliferation of microglia and infiltration of leukocytes are the most fundamental signs of CNS inflammation 4,5 . Increasing evidence suggests that the release of reactive oxygen species (ROS), interleukin‐6 (IL‐6), tumor necrosis factor‐alpha (TNF‐α), interferon‐γ (IFN‐γ), and other inflammatory factors during inflammation not only regulates the inflammatory process of CNS diseases but also affects the electrophysiological properties of neurons, astrocyte membranes and mitochondrial membranes, initiating the mitochondrial apoptosis pathway and exacerbating neuronal apoptosis and necrosis, leading to secondary brain damage 6–8 …”

Section: Introductionmentioning

confidence: 99%

Biological role of mitochondrial TLR4‐mediated NF‐κB signaling pathway in central nervous system injury

Wu,

Song,

Wang

et al. 2024

Cell Biochemistry & Function

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Previous studies suggested that central nervous system injury is often accompanied by the activation of Toll‐like receptor 4/NF‐κB pathway, which leads to the upregulation of proapoptotic gene expression, causes mitochondrial oxidative stress, and further aggravates the inflammatory response to induce cell apoptosis. Subsequent studies have shown that NF‐κB and IκBα can directly act on mitochondria. Therefore, elucidation of the specific mechanisms of NF‐κB and IκBα in mitochondria may help to discover new therapeutic targets for central nervous system injury. Recent studies have suggested that NF‐κB (especially RelA) in mitochondria can inhibit mitochondrial respiration or DNA expression, leading to mitochondrial dysfunction. IκBα silencing will cause reactive oxygen species storm and initiate the mitochondrial apoptosis pathway. Other research results suggest that RelA can regulate mitochondrial respiration and energy metabolism balance by interacting with p53 and STAT3, thus initiating the mitochondrial protection mechanism. IκBα can also inhibit apoptosis in mitochondria by interacting with VDAC1 and other molecules. Regulating the biological role of NF‐κB signaling pathway in mitochondria by targeting key proteins such as p53, STAT3, and VDAC1 may help maintain the balance of mitochondrial respiration and energy metabolism, thereby protecting nerve cells and reducing inflammatory storms and death caused by ischemia and hypoxia.

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P2X7 Receptor and Purinergic Signaling: Orchestrating Mitochondrial Dysfunction in Neurodegenerative Diseases

Abstract: Visual Abstract

Cited by 15 publications

References 260 publications

Hypoxia promotes temozolomide resistance in glioblastoma cells via ROS- mediated up-regulation of TRPM2

Hypoxia promotes temozolomide resistance in glioblastoma cells via ROS- mediated up-regulation of TRPM2

Next Generation Sequencing and Electromyography Reveal the Involvement of the P2RX6 Gene in Myopathy

Biological role of mitochondrial TLR4‐mediated NF‐κB signaling pathway in central nervous system injury

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