Peripheral Benzodiazepine Receptor/Translocator Protein Global Knock-out Mice Are Viable with No Effects on Steroid Hormone Biosynthesis

Tu, Lan N.; Morohaku, Kanako; Manna, Pulak R.; Pelton, Susanne H.; Butler, Walter; Stocco, Douglas M.; Selvaraj, Vimal

doi:10.1074/jbc.m114.578286

Cited by 211 publications

(224 citation statements)

References 68 publications

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“…Tmem178 is proposed as a negative regulator of macrophage activation and Ca 2+ signaling at the ER level (114), and is reduced in Tspo -/-mice. Conversely, there are increased levels of Zbtb7b, which is associated with T-cell maturation (115) and regulates the development of Natural Killer T (NKT) cells (116) and ties in the Tu et al study (110) with the recent work by Banati et al (32), who observed an increase in NKT cells present during haematological analysis in female Tspo -/-mice. TSPO has previously been reported as having antiretroviral activity by inhibiting Env protein expression (117).…”

Section: Tspo -/-Knockout Mice: New Insights Of An Old Functionmentioning

confidence: 80%

“…Recently, however, a number of studies from independent groups have reported that TSPO global knock out mice are viable and that loss of the protein has no effect on basal steroid hormone biosynthesis (32,35,110,111). These studies not only question the role TSPO holds in steroidogenesis but contrast early attempts to generate Tspo -/-knockout mice, which resulted in embryonic lethality (5).…”

Section: Tspo -/-Knockout Mice: New Insights Of An Old Functionmentioning

confidence: 87%

“…However, it is important to consider that compensatory mechanisms may play an important part in ensuring ongoing steroidogenesis in a TSPO null setting, and these may be different in the various strains, which may be attributed to methodology as highlighted already. In both global and conditional Tspo knock-out studies, several genes involved in steroidogenic processes were found to be upregulated including Cyp21a2 (110), Abca2 (110), and Scarb1 (111) in the adrenal glands and Lhcgr (111) in the testes ( TSPO is also attributed to immune regulation, with elevated expression observed in microglia and macrophages. Recently it was highlighted that TSPO is involved in cholesterol trafficking in macrophages, since its overexpression leads to increased transcription of proteins involved in cholesterol efflux, ACBA1 (ATP-binding cassette A1), PPARα (peroxisome-proliferator-activated receptor α) and LXRα (liver X receptor α), and corresponds with increased efflux of cholesterol to acceptors (113).…”

Section: Tspo -/-Knockout Mice: New Insights Of An Old Functionmentioning

confidence: 99%

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TSPO: kaleidoscopic 18-kDa amid biochemical pharmacology, control and targeting of mitochondria

Gatliff

Campanella

2016

Biochemical Journal

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The 18-kDa translocator protein (TSPO) localizes in the outer mitochondrial membrane (OMM) of cells and is readily up-regulated under various pathological conditions such as cancer, inflammation, mechanical lesions and neurological diseases. Able to bind with high affinity synthetic and endogenous ligands, its core biochemical function resides in the translocation of cholesterol into the mitochondria influencing the subsequent steps of (neuro-)steroid synthesis and systemic endocrine regulation. Over the years, however, TSPO has also been linked to core cellular processes such as apoptosis and autophagy. It interacts and forms complexes with other mitochondrial proteins such as the voltage-dependent anion channel (VDAC) via which signalling and regulatory transduction of these core cellular events may be influenced. Despite nearly 40 years of study, the precise functional role of TSPO beyond cholesterol trafficking remains elusive even though the recent breakthroughs on its high-resolution crystal structure and contribution to quality-control signalling of mitochondria. All this along with a captivating pharmacological profile provides novel opportunities to investigate and understand the significance of this highly conserved protein as well as contribute the development of specific therapeutics as presented and discussed in the present review.

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Section: Tspo -/-Knockout Mice: New Insights Of An Old Functionmentioning

confidence: 80%

Section: Tspo -/-Knockout Mice: New Insights Of An Old Functionmentioning

confidence: 87%

Section: Tspo -/-Knockout Mice: New Insights Of An Old Functionmentioning

confidence: 99%

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TSPO: kaleidoscopic 18-kDa amid biochemical pharmacology, control and targeting of mitochondria

Gatliff

Campanella

2016

Biochemical Journal

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“…TSPO/PBR was referred to as PBR until 2006, when it was renamed due to its potential role in translocation of cholesterol from the outer to the inner mitochondrial membrane [5]. Recent studies, however, challenge the direct involvement of TSPO/PBR in cholesterol transport and steroidogenesis [6][7][8]. At the same time, TSPO/PBR has been implicated in several biological functions [9], including mitochondrial respiration [10], cell proliferation [11], immunomodulation and apoptosis [12,13].…”

Section: The Tspo/pbr Proteinmentioning

confidence: 99%

Structure of the mammalian TSPO/PBR protein

Jaremko

Jaipuria

et al. 2015

Biochemical Society Transactions

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The 3D structure of the 18-kDa transmembrane (TM) protein TSPO (translocator protein)/PBR (peripheral benzodiazepine receptor), which contains a binding site for benzodiazepines, is important to better understand its function and regulation by endogenous and synthetic ligands. We have recently determined the structure of mammalian TSPO/PBR in complex with the diagnostic ligand PK11195 [1-(2-chlorophenyl)-N-methyl-N-(1-methylpropyl)-3-isoquinolinecarboxamide; Science 343, 1363-1366], providing for the first time atomic-level insight into the conformation of this protein, which is up-regulated in various pathological conditions including Alzheimer's disease and Parkinson's disease. Here, we review the studies which have probed the structural properties of mammalian TSPO/PBR as well as the homologues bacterial tryptophan-rich sensory proteins (TspOs) over the years and provide detailed insight into the 3D structure of mouse TSPO (mTSPO)/PBR in complex with PK11195.

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“…Ϫ/Ϫ Mice-Generation and validation of Tspo Ϫ/Ϫ mice has been previously described (7). Animals were maintained in accordance with the National Institutes of Health Guide for the Care and Use of Laboratory Animals, and the Institutional Animal Care and Use Committee of Cornell University approved all procedures.…”

Section: Tspomentioning

confidence: 99%

Mitochondrial Translocator Protein (TSPO) Function Is Not Essential for Heme Biosynthesis

Zhao

Mukai

et al. 2016

Journal of Biological Chemistry

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Function of the mammalian translocator protein (TSPO; previously known as the peripheral benzodiazepine receptor) remains unclear because its presumed role in steroidogenesis and mitochondrial permeability transition established using pharmacological methods has been refuted in recent genetic studies. Protoporphyrin IX (PPIX) is considered a conserved endogenous ligand for TSPO. In bacteria, TSPO was identified to regulate tetrapyrrole metabolism and chemical catalysis of PPIX in the presence of light, and in vertebrates, TSPO function has been linked to porphyrin transport and heme biosynthesis. Positive correlation between high TSPO expression in cancer cells and susceptibility to photodynamic therapy based on their increased ability to convert the precursor 5-aminolevulinic acid (ALA) to PPIX appeared to reinforce this mechanism. In this study, we used TSPO knock-out (Tspo ؊/؊ ) mice, primary cells, and different tumor cell lines to examine the role of TSPO in erythropoiesis, heme levels, PPIX biosynthesis, phototoxic cell death, and mitochondrial bioenergetic homeostasis. In contrast to expectations, our results demonstrate that TSPO deficiency does not adversely affect erythropoiesis, heme biosynthesis, bioconversion of ALA to PPIX, and porphyrin-mediated phototoxic cell death. TSPO expression levels in cancer cells do not correlate with their ability to convert ALA to PPIX. In fibroblasts, we observed that TSPO deficiency decreased the oxygen consumption rate and mitochondrial membrane potential (⌬⌿m) indicative of a cellular metabolic shift, without a negative impact on porphyrin biosynthetic capability. Based on these findings, we conclude that mammalian TSPO does not have a critical physiological function related to PPIX and heme biosynthesis.Mammalian translocator protein (TSPO), 2 previously known as the peripheral benzodiazepine receptor (1), is a highly conserved protein enriched in the outer mitochondrial membrane (2). Despite extensive efforts to characterize TSPO, its precise physiological function remains elusive (3, 4). High levels of TSPO expression in steroidogenic cells, its localization to the outer mitochondrial membrane, and increased steroid production upon pharmacological binding led to the primary prospective model that TSPO was a mitochondrial cholesterol transporter essential for steroidogenesis (5). In recent studies using precise genetic tools, we and others have systematically refuted the involvement of TSPO in this process (6 -10). Similarly, copurification of TSPO with putative members of the mitochondrial permeability transition pore (MPTP) (11) and effects mediated by TSPO binding drugs on modulating apoptosis (12, 13) resulted in a secondary model that TSPO was associated with MPTP function and cell death (14). Again, recent discovery of the molecular identity of MPTP (15) Binding of porphyrins to TSPO has been a consistent property reported in bacteria (18), plants (19), and animals (17). In Rhodobacter sphaeroides, TSPO was found localized to the outer membrane (18) and pl...

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Peripheral Benzodiazepine Receptor/Translocator Protein Global Knock-out Mice Are Viable with No Effects on Steroid Hormone Biosynthesis

Cited by 211 publications

References 68 publications

TSPO: kaleidoscopic 18-kDa amid biochemical pharmacology, control and targeting of mitochondria

TSPO: kaleidoscopic 18-kDa amid biochemical pharmacology, control and targeting of mitochondria

Structure of the mammalian TSPO/PBR protein

Mitochondrial Translocator Protein (TSPO) Function Is Not Essential for Heme Biosynthesis

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