Classical and Novel TSPO Ligands for the Mitochondrial TSPO can Modulate Nuclear Gene Expression: Implications for Mitochondrial Retrograde Signaling

Yasin, Nasra; Veenman, Leo; Singh, Sukhdev; Azrad, Maya; Bode, Julia; Vainshtein, Alex; Caballero, Bea; Marek, Ilan; Gavish, Moshe

doi:10.20944/preprints201612.0068.v2

Cited by 7 publications

(6 citation statements)

References 14 publications

(24 reference statements)

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“…The immunofluorescence analysis confirmed the presence of the investigated proteins and added details about their subcellular localization ( Figure 2 F). As expected, TSPO was detected mainly in the perinuclear region, as reported previously [ 47 ], and displayed good co-localization with mitochondria [ 50 , 51 ]. StAR appeared homogeneously distributed in cells, in agreement with its known dynamic shuttling between cytosol and mitochondria [ 20 , 23 ].The mitochondrial enzyme CYP11A1 presented perinuclear localization too, and the fluorescence intensity was higher in HMC3 than in C20 cells, in accordance with Western blot data ( Figure 2 E).…”

Section: Resultssupporting

confidence: 87%

De novo Neurosteroidogenesis in Human Microglia: Involvement of the 18 kDa Translocator Protein

Germelli

Pozzo

Giacomelli

et al. 2021

IJMS

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Neuroactive steroids are potent modulators of microglial functions and are capable of counteracting their excessive reactivity. This action has mainly been ascribed to neuroactive steroids released from other sources, as microglia have been defined unable to produce neurosteroids de novo. Unexpectedly, immortalized murine microglia recently exhibited this de novo biosynthesis; herein, de novo neurosteroidogenesis was characterized in immortalized human microglia. The results demonstrated that C20 and HMC3 microglial cells constitutively express members of the neurosteroidogenesis multiprotein machinery—in particular, the transduceosome members StAR and TSPO, and the enzyme CYP11A1. Moreover, both cell lines produce pregnenolone and transcriptionally express the enzymes involved in neurosteroidogenesis. The high TSPO expression levels observed in microglia prompted us to assess its role in de novo neurosteroidogenesis. TSPO siRNA and TSPO synthetic ligand treatments were used to reduce and prompt TSPO function, respectively. The TSPO expression downregulation compromised the de novo neurosteroidogenesis and led to an increase in StAR expression, probably as a compensatory mechanism. The pharmacological TSPO stimulation the de novo neurosteroidogenesis improved in turn the neurosteroid-mediated release of Brain-Derived Neurotrophic Factor. In conclusion, these results demonstrated that de novo neurosteroidogenesis occurs in human microglia, unravelling a new mechanism potentially useful for future therapeutic purposes.

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Section: Resultssupporting

confidence: 87%

De novo Neurosteroidogenesis in Human Microglia: Involvement of the 18 kDa Translocator Protein

Germelli

Pozzo

Giacomelli

et al. 2021

IJMS

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“…The involvement of TSPO in these diseases was expected because TSPO generates reactive oxygen species that form mPTP - the enigmatic gatekeeper of apoptosis and necroptosis, decreases ATP synthesis, and eventually results in cell death ( Veenman et al, 2010 ; Kinnally et al, 2011 ; Veenman et al, 2018 ; Zeineh et al, 2019 ; Dimitrova-Shumkovska et al, 2020 ). Besides our predictions of TSPO functions, a recent study by Yasin et al reported that TSPO regulates nuclear gene expression mainly through the mitochondria-to-nucleus signalling pathway ( Yasin et al, 2017 ). Our analysis reporting the roles of TSPO in various disease states contributes to the existing knowledge of the effect of TSPO on gene expression.…”

Section: Discussionsupporting

confidence: 54%

Bioinformatic Analyses of Canonical Pathways of TSPOAP1 and its Roles in Human Diseases

Kumar

Alam

Lee

et al. 2021

Front. Mol. Biosci.

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TSPO-associated protein 1 (TSPOAP1) is a cytoplasmic protein and is closely associated with its mitochondrial transmembrane protein partner translocator protein (TSPO). To decipher the canonical signalling pathways of TSPOAP1, its role in human diseases and disorders, and relationship with TSPO; expression analyses of TSPOAP1- and TSPO-associated human genes were performed by Qiagen Ingenuity Pathway Analysis (IPA). In the expression analysis, necroptosis and sirtuin signalling pathways, mitochondrial dysfunction, and inflammasome were the top canonical pathways for both TSPOAP1 and TSPO, confirming the close relationship between these two proteins. A distribution analysis of common proteins in all the canonical pathways predicted for TSPOAP1 revealed that tumor necrosis factor receptor 1 (TNFR1), vascular cell adhesion molecule 1 (VCAM1), cyclic AMP response element-binding protein 1 (CREB1), T-cell receptor (TCR), nucleotide-binding oligomerization domain, leucine-rich repeat and pyrin domain containing 3 (NLRP3), DNA-dependent protein kinase (DNA-PK or PRKDC), and mitochondrial permeability transition pore (mPTP) were the major interaction partners of TSPOAP1, highlighting the role of TSPOAP1 in inflammation, particularly neuroinflammation. An analysis of the overlap between TSPO and TSPOAP1 Homo sapiens genes and top-ranked canonical pathways indicated that TSPO and TSPOAP1 interact via voltage-dependent anion-selective channels (VDAC1/2/3). A heat map analysis indicated that TSPOAP1 has critical roles in inflammatory, neuroinflammatory, psychiatric, and metabolic diseases and disorders, and cancer. Taken together, this information improves our understanding of the mechanism of action and biological functions of TSPOAP1 as well as its relationship with TSPO; furthermore, these results could provide new directions for in-depth functional studies of TSPOAP1 aimed at unmasking its detailed functions.

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“…Calcium release, ATP production and ROS are part of the retrograde mitochondria-nucleus signaling pathway. Interestingly, Gavish and colleagues recently showed that TSPO drug ligands modulate nuclear gene expression, in addition to directly increasing TSPO expression levels, thus further implicating TSPO in mitochondrial retrograde signaling [ 57 , 58 ]. Our work supports these findings and extends them by demonstrating that TSPO itself is part of the mitochondrial–nuclear signaling pathway regulating nuclear gene expression.…”

Section: Discussionmentioning

confidence: 99%

Mitochondrial TSPO Deficiency Triggers Retrograde Signaling in MA-10 Mouse Tumor Leydig Cells

Fan

Papadopoulos

2020

IJMS

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The mitochondrial translocator protein (TSPO) has been shown to bind cholesterol with high affinity and is involved in mediating its availability for steroidogenesis. We recently reported that targeted Tspo gene deletion in MA-10 mouse tumor Leydig cells resulted in reduced cAMP-stimulated steroid formation and significant reduction in the mitochondrial membrane potential (ΔΨm) compared to control cells. We hypothesized that ΔΨm reduction in the absence of TSPO probably reflects the dysregulation and/or maintenance failure of some basic mitochondrial function(s). To explore the consequences of TSPO depletion via CRISPR-Cas9-mediated deletion (indel) mutation in MA-10 cells, we assessed the transcriptome changes in TSPO-mutant versus wild-type (Wt) cells using RNA-seq. Gene expression profiles were validated using real-time PCR. We report herein that there are significant changes in nuclear gene expression in Tspo mutant versus Wt cells. The identified transcriptome changes were mapped to several signaling pathways including the regulation of membrane potential, calcium signaling, extracellular matrix, and phagocytosis. This is a retrograde signaling pathway from the mitochondria to the nucleus and is probably the result of changes in expression of several transcription factors, including key members of the NF-κB pathway. In conclusion, TSPO regulates nuclear gene expression through intracellular signaling. This is the first evidence of a compensatory response to the loss of TSPO with transcriptome changes at the cellular level.

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Classical and Novel TSPO Ligands for the Mitochondrial TSPO can Modulate Nuclear Gene Expression: Implications for Mitochondrial Retrograde Signaling

Cited by 7 publications

References 14 publications

De novo Neurosteroidogenesis in Human Microglia: Involvement of the 18 kDa Translocator Protein

De novo Neurosteroidogenesis in Human Microglia: Involvement of the 18 kDa Translocator Protein

Bioinformatic Analyses of Canonical Pathways of TSPOAP1 and its Roles in Human Diseases

Mitochondrial TSPO Deficiency Triggers Retrograde Signaling in MA-10 Mouse Tumor Leydig Cells

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