The polypeptide diazepam-binding inhibitor and a higher affinity mitochondrial peripheral-type benzodiazepine receptor sustain constitutive steroidogenesis in the R2C Leydig tumor cell line.

Garnier, Martine; Boujrad, Noureddine; Ogwuegbu, S. O.; Hudson, James R.; Papadopoulos, Vassilios

doi:10.1016/s0021-9258(17)31762-3

Cited by 79 publications

(8 citation statements)

References 44 publications

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“…[5][6][7][8][9] TSPO has been shown to be associated with a number of biological processes that are signatures for tissues' well-being, including cell proliferation, apoptosis, steroidogenesis, and immunomodulation. [5][6][7] While it has been used as a target for nuclear imaging in humans, 10,11 TSPO's importance to steroid production and cholesterol transport continue to make it an important biomarker for targeted imaging that has not met its full potential. [12][13][14] Recognizing the importance of TSPO, our laboratory has reported the synthesis and biological evaluation of several small molecule optical TSPO imaging agents as well as one dendrimeric agent.…”

Section: Introductionmentioning

confidence: 99%

A self-internalizing mitochondrial TSPO targeting imaging probe for fluorescence, MRI and EM

et al. 2014

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Advances in probes for cellular imaging have driven discoveries in biology and medicine. Primarily, antibodies and small molecules have been made for contrast enhancement of specific proteins. The development of new dendrimer-based tools offers opportunities to tune cellular internalization and targeting, image multiple modalities in the same molecule and explore therapeutics. The translocator protein (TSPO) offers an ideal target to develop dendrimer tools because it is well characterized and implicated in a number of disease states. The TSPO-targeted dendrimers reported here, primarily ClPhIQ-PAMAM-Gd-Liss, are cell membrane permeable nanoparticles that enable labeling of TSPO and provide contrast in fluorescence, electron microscopy and magnetic resonance imaging. The molecular binding affinity for TSPO was found to be 0.51 μM, 3 times greater than the monomeric agents previously demonstrated in our laboratory. The relaxivity per Gd 3+ of the ClPhIQ 23-PAMAM-Gd 18 dendrimer was 7.7 and 8.0 mM −1 s −1 for r 1 and r 2 respectively, approximately double that of the clinically used monomeric Gd 3+ chelates. In vitro studies confirmed molecular selectively for labeling TSPO in the mitochondria of C6 rat glioma and MDA-MB-231 cell lines. Fluorescence co-registration with Mitotracker Green® and increased contrast of osmium-staining in electron microscopy confirmed mitochondrial labeling of these TSPO-targeted agents. Taken collectively these experiments demonstrate the versatility of conjugation of our PAMAM dendrimeric chemistry to allow multimodality agents to be prepared. These agents target organelles and use complementary imaging modalities in vitro, potentially allowing disease mechanism studies with high sensitivity and high resolution techniques.

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Section: Introductionmentioning

confidence: 99%

A self-internalizing mitochondrial TSPO targeting imaging probe for fluorescence, MRI and EM

et al. 2014

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“…In mammals, TSPO evolution has led to an apparent regulatory role in the specialized function of cholesterol transport in steroidogenic tissues while maintaining the ancient partnership with VDAC/porin and adding on many more protein partners to form a large complex to accomplish and regulate this critical function (Liu et al 2006 ; Rone et al 2009 , 2012 ). As TSPO gained the ability to bind 14-3-3 proteins (Aghazadeh et al 2012 , 2014 ) and ACBD proteins such as DBI/ACBP/ACBD1 (Guidotti et al 1983 ; Papadopoulos et al 1991 , 1992 ; Papadopoulos 1993 ; Garnier et al 1994a ; Rone et al 2009 ) or ACBD3/PAP7 (Li et al 2001 ; Liu et al 2003 ; Fan et al 2010 ), evidence supports a gain of function from these new partnerships. TSPO, with its binding partners, exhibits significant involvement in many areas of metabolism and stress related activity.…”

Section: Discussionmentioning

confidence: 98%

“…This suggests that DBI/ACBD1, as well as ACBD3, could be involved in the regulation of cholesterol transport into mammalian mitochondria. DBI was localized to the ER, Golgi, and OMM in rat testis (Schultz et al 1992 ) where it would have the opportunity to bind to TSPO, and chemical crosslinking studies demonstrated that DBI binds directly to TSPO (Garnier et al 1994a ). The interaction between DBI and TSPO has been deemed critical for hormone stimulation of adrenal steroidogenesis [reviewed in (Fan et al 2010 )], and most of the reported connections between TSPO and DBI involve this metabolic process.…”

Section: Tspo Binding Partnersmentioning

confidence: 99%

TSPO protein binding partners in bacteria, animals, and plants

Hiser

Montgomery

Ferguson‐Miller

2021

J Bioenerg Biomembr

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The ancient membrane protein TSPO is phylogenetically widespread from archaea and bacteria to insects, vertebrates, plants, and fungi. TSPO’s primary amino acid sequence is only modestly conserved between diverse species, although its five transmembrane helical structure appears mainly conserved. Its cellular location and orientation in membranes have been reported to vary between species and tissues, with implications for potential diverse binding partners and function. Most TSPO functions relate to stress-induced changes in metabolism, but in many cases it is unclear how TSPO itself functions—whether as a receptor, a sensor, a transporter, or a translocator. Much evidence suggests that TSPO acts indirectly by association with various protein binding partners or with endogenous or exogenous ligands. In this review, we focus on proteins that have most commonly been invoked as TSPO binding partners. We suggest that TSPO was originally a bacterial receptor/stress sensor associated with porphyrin binding as its most ancestral function and that it later developed additional stress-related roles in eukaryotes as its ability to bind new partners evolved.

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“…In C6-2B glioma cells, an ACBD1-dependent formation of mitochondrial pregnenolone was described [ 32 ]. The depletion of ACBD1 in MA-10 and R2C Leydig cells led to decreased human chorion gonadotropin-stimulated steroidogenesis and decreased progesterone production, respectively [ 33 , 34 ]. Similarly to ACBD3, ACBD1 also binds TSPO at the outer and inner mitochondrial membrane contact sites and stimulates cholesterol transport into mitochondria.…”

Section: Discussionmentioning

confidence: 99%

Knock-Out of ACBD3 Leads to Dispersed Golgi Structure, but Unaffected Mitochondrial Functions in HEK293 and HeLa Cells

Danhelovska

Zdrazilova

Stufkova

et al. 2021

IJMS

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The Acyl-CoA-binding domain-containing protein (ACBD3) plays multiple roles across the cell. Although generally associated with the Golgi apparatus, it operates also in mitochondria. In steroidogenic cells, ACBD3 is an important part of a multiprotein complex transporting cholesterol into mitochondria. Balance in mitochondrial cholesterol is essential for proper mitochondrial protein biosynthesis, among others. We generated ACBD3 knock-out (ACBD3-KO) HEK293 and HeLa cells and characterized the impact of protein absence on mitochondria, Golgi, and lipid profile. In ACBD3-KO cells, cholesterol level and mitochondrial structure and functions are not altered, demonstrating that an alternative pathway of cholesterol transport into mitochondria exists. However, ACBD3-KO cells exhibit enlarged Golgi area with absence of stacks and ribbon-like formation, confirming the importance of ACBD3 in Golgi stacking. The glycosylation of the LAMP2 glycoprotein was not affected by the altered Golgi structure. Moreover, decreased sphingomyelins together with normal ceramides and sphingomyelin synthase activity reveal the importance of ACBD3 in ceramide transport from ER to Golgi.

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The polypeptide diazepam-binding inhibitor and a higher affinity mitochondrial peripheral-type benzodiazepine receptor sustain constitutive steroidogenesis in the R2C Leydig tumor cell line.

Cited by 79 publications

References 44 publications

A self-internalizing mitochondrial TSPO targeting imaging probe for fluorescence, MRI and EM

A self-internalizing mitochondrial TSPO targeting imaging probe for fluorescence, MRI and EM

TSPO protein binding partners in bacteria, animals, and plants

Knock-Out of ACBD3 Leads to Dispersed Golgi Structure, but Unaffected Mitochondrial Functions in HEK293 and HeLa Cells

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