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Differential Regulation of Glial and Neuronal Functions by TSPO
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Differential Regulation of Glial and Neuronal Functions by TSPO

A special issue of Cells (ISSN 2073-4409). This special issue belongs to the section "Cell Signaling".

Deadline for manuscript submissions: closed (1 June 2020) | Viewed by 22942

Special Issue Editor

Dr. Leo Veenman

E-Mail Website
Guest Editor
Consorzio per Valutazioni Biologiche e Farmacologiche, Via Nicolò Putignani, 178, 70122 Bari, Italy
Interests: drug development; brain disease and injury; mitochondrial function; genomics/non-genomics
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

It is becoming more and more understood that the translocator protein (TSPO) can be targeted to treat neurological disorders. From its mitochondrial location, TSPO appears to modulate the generation of various molecules, as well as their transport over the outer mitochondrial membrane. Via these molecules, including Ca++, ATP, ROS, cholesterol, tetrapyrroles, and cytochrome c, TSPO can regulate mitochondria to cell nucleus signaling and the mitochondrial apoptosis cascade. Thereby, TSPO regulates basic cellular functions, including metabolism, gene expression, and programmed cell death, as well as inflammation, immune responses, cell proliferation, migration, adhesion, differentiation, regeneration, etc. These are essential functions associated with various brain disorders and their healing. Numerous synthetic TSPO ligands have been developed and their effects on such functions have been tested. For example, TSPO ligands can modulate the cell death of astrocytes and neurons, as well as microglia activation. Thus, TSPO ligands can be designed to reduce damage due to brain injury and disease. Moreover, by the modulation of neuronal differentiation and regeneration, TSPO ligands are capable of promoting the repair of neuronal damage. Interestingly, synthetic and natural ligands bind to various sites on TSPO. Thus, it appears that TSPO ligands can be applied to treat various aspects of brain disorders.

Dr. Leo Veenman
Guest Editor

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Keywords

  • TSPO
  • mitochondria
  • cell nucleus
  • gene expression
  • pathway analysis
  • metabolism
  • programmed cell death
  • inflammation
  • disease
  • injury
  • brain
  • astrocytes
  • microglia
  • neurons

Published Papers (5 papers)

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Research

23 pages, 5631 KiB  
Article
The VDAC1-based R-Tf-D-LP4 Peptide as a Potential Treatment for Diabetes Mellitus
by Srinivas Pittala, Idan Levy, Soumasree De, Swaroop Kumar Pandey, Nataly Melnikov, Tehila Hyman and Varda Shoshan-Barmatz
Cells 2020, 9(2), 481; https://doi.org/10.3390/cells9020481 - 19 Feb 2020
Cited by 16 | Viewed by 4191
Abstract
Diabetes mellitus is a metabolic disorder approaching epidemic proportions. Non-alcoholic fatty liver disease (NAFLD) regularly coexists with metabolic disorders, including type 2 diabetes, obesity, and cardiovascular disease. Recently, we demonstrated that the voltage-dependent anion channel 1 (VDAC1) is involved in NAFLD. VDAC1 is [...] Read more.
Diabetes mellitus is a metabolic disorder approaching epidemic proportions. Non-alcoholic fatty liver disease (NAFLD) regularly coexists with metabolic disorders, including type 2 diabetes, obesity, and cardiovascular disease. Recently, we demonstrated that the voltage-dependent anion channel 1 (VDAC1) is involved in NAFLD. VDAC1 is an outer mitochondria membrane protein that serves as a mitochondrial gatekeeper, controlling metabolic and energy homeostasis, as well as crosstalk between the mitochondria and the rest of the cell. It is also involved in mitochondria-mediated apoptosis. Here, we demonstrate that the VDAC1-based peptide, R-Tf-D-LP4, affects several parameters of a NAFLD mouse model in which administration of streptozotocin (STZ) and high-fat diet 32 (STZ/HFD-32) led to both type 2 diabetes (T2D) and NAFLD phenotypes. We focused on diabetes, showing that R-Tf-D-LP4 peptide treatment of STZ/HFD-32 fed mice restored the elevated blood glucose back to close to normal levels, and increased the number and average size of islets and their insulin content as compared to untreated controls. Similar results were obtained when staining the islets for glucose transporter type 2. In addition, the R-Tf-D-LP4 peptide decreased the elevated glucose levels in a mouse displaying obese, diabetic, and metabolic symptoms due to a mutation in the obese (ob) gene. To explore the cause of the peptide-induced improvement in the endocrine pancreas phenotype, we analyzed the expression levels of the proliferation marker, Ki-67, and found it to be increased in the islets of STZ/HFD-32 fed mice treated with the R-Tf-D-LP4 peptide. Moreover, peptide treatment of STZ/HFD-32 fed mice caused an increase in the expression of β-cell maturation and differentiation PDX1 transcription factor that enhances the expression of the insulin-encoding gene, and is essential for islet development, function, proliferation, and maintenance of glucose homeostasis in the pancreas. This increase occurred mainly in the β-cells, suggesting that the source of their increased number after R-Tf-D-LP4 peptide treatment was most likely due to β-cell proliferation. These results suggest that the VDAC1-based R-Tf-D-LP4 peptide has potential as a treatment for diabetes. Full article
(This article belongs to the Special Issue Differential Regulation of Glial and Neuronal Functions by TSPO)
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32 pages, 8375 KiB  
Article
Rewiring of Cancer Cell Metabolism by Mitochondrial VDAC1 Depletion Results in Time-Dependent Tumor Reprogramming: Glioblastoma as a Proof of Concept
by Tasleem Arif, Oriel Stern, Srinivas Pittala, Vered Chalifa-Caspi and Varda Shoshan-Barmatz
Cells 2019, 8(11), 1330; https://doi.org/10.3390/cells8111330 - 28 Oct 2019
Cited by 17 | Viewed by 4100
Abstract
Reprograming of the metabolism of cancer cells is an event recognized as a hallmark of the disease. The mitochondrial gatekeeper, voltage-dependent anion channel 1 (VDAC1), mediates transport of metabolites and ions in and out of mitochondria, and is involved in mitochondria-mediated apoptosis. Here, [...] Read more.
Reprograming of the metabolism of cancer cells is an event recognized as a hallmark of the disease. The mitochondrial gatekeeper, voltage-dependent anion channel 1 (VDAC1), mediates transport of metabolites and ions in and out of mitochondria, and is involved in mitochondria-mediated apoptosis. Here, we compared the effects of reducing hVDAC1 expression in a glioblastoma xenograft using human-specific si-RNA (si-hVDAC1) for a short (19 days) and a long term (40 days). Tumors underwent reprograming, reflected in rewired metabolism, eradication of cancer stem cells (CSCs) and differentiation. Short- and long-term treatments of the tumors with si-hVDAC1 similarly reduced the expression of metabolism-related enzymes, and translocator protein (TSPO) and CSCs markers. In contrast, differentiation into cells expressing astrocyte or neuronal markers was noted only after a long period during which the tumor cells were hVDAC1-depleted. This suggests that tumor cell differentiation is a prolonged process that precedes metabolic reprograming and the “disappearance” of CSCs. Tumor proteomics analysis revealing global changes in the expression levels of proteins associated with signaling, synthesis and degradation of proteins, DNA structure and replication and epigenetic changes, all of which were highly altered after a long period of si-hVDAC1 tumor treatment. The depletion of hVDAC1 greatly reduced the levels of the multifunctional translocator protein TSPO, which is overexpressed in both the mitochondria and the nucleus of the tumor. The results thus show that VDAC1 depletion-mediated cancer cell metabolic reprograming involves a chain of events occurring in a sequential manner leading to a reversal of the unique properties of the tumor, indicative of the interplay between metabolism and oncogenic signaling networks. Full article
(This article belongs to the Special Issue Differential Regulation of Glial and Neuronal Functions by TSPO)
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14 pages, 3122 KiB  
Article
Effects of Cigarette Smoke on TSPO-related Mitochondrial Processes
by Nidal Zeineh, Rafael Nagler, Martin Gabay, Abraham Weizman and Moshe Gavish
Cells 2019, 8(7), 694; https://doi.org/10.3390/cells8070694 - 10 Jul 2019
Cited by 16 | Viewed by 3897
Abstract
The 18 kDa translocator protein (TSPO) is an initiator of the mitochondrial apoptosis cascade. Cigarette smoke (CS) exposure provokes alterations in TSPO expression as well as upregulation of its related functions such as mitochondrial membrane potential (ΔψM) and reactive oxygen species [...] Read more.
The 18 kDa translocator protein (TSPO) is an initiator of the mitochondrial apoptosis cascade. Cigarette smoke (CS) exposure provokes alterations in TSPO expression as well as upregulation of its related functions such as mitochondrial membrane potential (ΔψM) and reactive oxygen species generation, which are associated with cell death. In the current study, H1299 lung cancer cell line exposed to CS for various time periods (30 mins, 60 mins and 120 mins) and TSPO expression and cell death processes were studied. CS exposure for 30 mins resulted in a non-significant increase in TSPO expression by 24% (p > 0.05 vs. control). CS exposure for 60 mins and 120 mins resulted in a significant increase by 43% (p < 0.05 vs. control) and by 47% (p < 0.01 vs. control), respectively. Furthermore, TSPO-related mitochondrial functions were upregulated at the 120 mins time point following CS exposure. TSPO expression is upregulated by CS, suggesting that TSPO plays a role in cell death processes induced by CS exposure. Alterations in TSPO-related cell death processes suggest that TSPO may be involved in the tissue damage caused by CS. Full article
(This article belongs to the Special Issue Differential Regulation of Glial and Neuronal Functions by TSPO)
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23 pages, 5343 KiB  
Article
Cortisol Excess-Mediated Mitochondrial Damage Induced Hippocampal Neuronal Apoptosis in Mice Following Cold Exposure
by Bin Xu, Li-min Lang, Shi-Ze Li, Jing-Ru Guo, Jian-Fa Wang, Di Wang, Li-Ping Zhang, Huan-Min Yang and Shuai Lian
Cells 2019, 8(6), 612; https://doi.org/10.3390/cells8060612 - 18 Jun 2019
Cited by 36 | Viewed by 5930
Abstract
Cold stress can induce neuronal apoptosis in the hippocampus, but the internal mechanism involving neuronal loss induced by cold stress is not clear. In vivo, male and female C57BL/6 mice were exposed to 4 °C, 3 h per day for 1 week. In [...] Read more.
Cold stress can induce neuronal apoptosis in the hippocampus, but the internal mechanism involving neuronal loss induced by cold stress is not clear. In vivo, male and female C57BL/6 mice were exposed to 4 °C, 3 h per day for 1 week. In vitro, HT22 cells were treated with different concentrations of cortisol (CORT) for 3 h. In vivo, CORT levels in the hippocampus were measured using ELISA, western blotting, and immunohistochemistry to assess the neuronal population and oxidation of the hippocampus. In vitro, western blotting, immunofluorescence, flow cytometry, transmission electron microscopy, and other methods were used to characterize the mechanism of mitochondrial damage induced by CORT. The phenomena of excessive CORT-mediated oxidation stress and neuronal apoptosis were shown in mouse hippocampus tissue following cold exposure, involving mitochondrial oxidative stress and endogenous apoptotic pathway activation. These processes were mediated by acetylation of lysine 9 of histone 3, resulting in upregulation involving Adenosine 5‘-monophosphate (AMP)-activated protein kinase (APMK) phosphorylation and translocation of Nrf2 to the nucleus. In addition, oxidation in male mice was more severe. These findings provide a new understanding of the underlying mechanisms of the cold stress response and explain the apoptosis process induced by CORT, which may influence the selection of animal models in future stress-related studies. Full article
(This article belongs to the Special Issue Differential Regulation of Glial and Neuronal Functions by TSPO)
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14 pages, 1148 KiB  
Article
Inhibitory Effects of the Two Novel TSPO Ligands 2-Cl-MGV-1 and MGV-1 on LPS-induced Microglial Activation
by Sheelu Monga, Rafi Nagler, Rula Amara, Abraham Weizman and Moshe Gavish
Cells 2019, 8(5), 486; https://doi.org/10.3390/cells8050486 - 22 May 2019
Cited by 26 | Viewed by 4260
Abstract
The 18 kDa translocator protein (TSPO) ligands 2-Cl-MGV-1 and MGV-1 can attenuate cell death of astrocyte-like cells (U118MG) and induce differentiation of neuronal progenitor cells (PC-12). Lipopolysaccharide (LPS) is a bacterial membrane endotoxin that activates cellular inflammatory pathways by releasing pro-inflammatory molecules, including [...] Read more.
The 18 kDa translocator protein (TSPO) ligands 2-Cl-MGV-1 and MGV-1 can attenuate cell death of astrocyte-like cells (U118MG) and induce differentiation of neuronal progenitor cells (PC-12). Lipopolysaccharide (LPS) is a bacterial membrane endotoxin that activates cellular inflammatory pathways by releasing pro-inflammatory molecules, including cytokines and chemokines. The aim of the present study was to assess the immuno-modulatory effect of TSPO ligands in activated microglial cells. We demonstrated that the TSPO ligands 2-Cl-MGV-1 and MGV-1 can prevent LPS-induced activation of microglia (BV-2 cell line). Co-treatment of LPS (100 ng/mL) with these TSPO ligands (final concentration- 25 µM) reduces significantly the LPS-induced release of interleukin-6 (IL-6) from 16.9-fold to 2.5-fold, IL-β from 8.3-fold to 1.6-fold, interferon-γ from 16.0-fold to 2.2-fold, and tumor necrosis factor-α from 16.4-fold to 1.8-fold. This anti-inflammatory activity seems to be achieved by inhibition of NF-κB p65 activation. Assessment of initiation of ROS generation and cell metabolism shows significant protective effects of these two novel TSPO ligands. The IL-10 and IL-13 levels were not affected by any of the TSPO ligands. Thus, it appears that the ligands suppress the LPS-induced activation of some inflammatory responses of microglia. Such immunomodulatory effects may be relevant to the pharmacotherapy of neuro-inflammatory diseases. Full article
(This article belongs to the Special Issue Differential Regulation of Glial and Neuronal Functions by TSPO)
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