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The 18 kDa Translocator Protein (TSPO): Cholesterol Trafficking and the Biology of a Prognostic and Therapeutic Mitochondrial Target

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Molecular Basis for Mitochondrial Signaling

Part of the book series: Biological and Medical Physics, Biomedical Engineering ((BIOMEDICAL))

Abstract

Mitochondria serve a plethora of functions, beyond the essential production of ATP, that are intimately involved in the definition of cellular physiology and pathology. These roles include the buffering and decoding of signalling, induction of programmed cell death and steroidogenesis.

The biochemical pathways that define steroidgenesis have been largely investigated, but proteins and pathways regulating its efficiency are not yet fully understood. The 18 kDa protein translocator protein (TSPO), named so for its ability to shuttle cholesterol into the mitochondria feeding the synthesis of pregnenolone, plays an active part in this process. However its relevance for mitochondrial, and hence cellular, homeostasis is likely broader encompassing other processes.

TSPO is a highly inducible protein which interacts with the voltage-dependent anion channel 1 (VDAC1) and is associated with intracellular redox stress, thereby interfering with the autophagic quality control mechanisms of mitochondria (mitophagy). Functioning as a stress-response element, TSPO holds a remarkably conserved sequence and structure throughout evolution. Through its associations with a wide range of cellular and pathological processes, it naturally represents a prognostic and therapeutic target to infer human and animal welfare. In this chapter, we shall recapitulate the current literature available on TSPO, discussing its compelling science and presenting the most recent breakthroughs on its structure and function. The overall goal is to illustrate the ways in which TSPO partakes in mitochondrial and cellular processes.

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Abbreviations

Å:

Ångström

ACBD:

Acyl-coenzyme A binding domain containing

ACTH:

Adrenocorticotropin

AD:

Alzheimer’s disease

ALAS-1:

5′-aminolevulinate synthase 1

ANT:

Adenine nucleotide transporter

AP:

Activator protein

Atg8:

Autophagy related protein 8

Bcl-2:

B-cell lymphoma 2

BcTSPO:

Bacillus cereus TspO

cAMP:

Cyclic adenosine monophosphate

CARC:

Cholesterol consensus domain

CNS:

Central nervous system

CRAC:

Cholesterol recognition amino acid consensus

CRF:

Corticotropin-releasing factor

DBI:

Diazepam-binding inhibitor

EM:

Electron microscopy

ERα:

Oestrogen receptor α

Ets:

E26 oncogene homolog

FCCP:

Carbonyl cyanide p-(trifluoromethoxy) phenylhydrazone

GABA:

Gamma-aminobutyric acid

HIV:

Human immunodeficiency virus

HPA:

Hypothalamic-pituitary-adrenal

KO:

Knockout

I/R:

Ischemia/reperfusion

LC3:

Microtubule-associated protein light chain 3

mPTP:

Mitochondrial permeability transition pore

MS:

Multiple sclerosis

mTSPO:

Mammalian TSPO

NAT:

Natural antisense transcript

NLRP3:

Nod-like receptor family, pyrin domain containing 3

NMR:

Nuclear magnetic resonance

NOX:

NADPH oxidase

OMM:

Outer mitochondrial membrane

PBR:

Peripheral-type benzodiazepine receptor

PD:

Parkinson’s disease

PEPCK:

Phosphoenolpyruvate carboxykinase

PET:

Positron emission tomography

PGC-1α:

PPAR-gamma coactivator-1 α

PINK1:

PTEN-induced putative kinase 1

PKA:

Protein kinase A

PKCε:

Protein kinase Cε

PMA:

Phorbol-12-myristate 13-acetate

PPAR:

Peroxisome proliferator-activated receptor

PpIX:

Protoporphyrin IX

ROS:

Reactive oxygen species

RsTspO:

R. sphaeroides TspO

Sp:

Specificity protein

StAR:

Steroidogenic acute response protein

STAT:

Signal transducer and activator of transcription

TM:

Transmembrane (number assignment for helices in TSPO structure)

TSPO:

Translocator protein

TspO:

Tryptophan-rich sensory protein

VDAC:

Voltage gated anion channel

WT:

Wild type

References

  • Aghazadeh Y, Rone MB, Blonder J, Ye X, Veenstra TD, Hales DB, Culty M, Papadopoulos V (2012) Hormone-induced 14-3-3γ adaptor protein regulates steroidogenic acute regulatory protein activity and steroid biosynthesis in MA-10 Leydig cells. J Biol Chem 287:15380–15394

    Article  Google Scholar 

  • Aghazadeh Y, Martinez-Arguelles DB, Fan J, Culty M, Papadopoulos V (2014) Induction of androgen formation in the male by a TAT-VDAC1 fusion peptide blocking 14-3-3ɛ protein adaptor and mitochondrial VDAC1 interactions. Mol Ther J Am Soc Gene Ther 22:1779–1791

    Article  Google Scholar 

  • Alho H, Costa E, Ferrero P, Fujimoto M, Cosenza-Murphy D, Guidotti A (1985) Diazepam-binding inhibitor: a neuropeptide located in selected neuronal populations of rat brain. Science 229:179–182

    Article  ADS  Google Scholar 

  • Alho H, Harjuntausta T, Schultz R, Pelto-Huikko M, Bovolin P (1991) Immunohistochemistry of diazepam binding inhibitor (DBI) in the central nervous system and peripheral organs: its possible role as an endogenous regulator of different types of benzodiazepine receptors. Neuropharmacology 30:1381–1386

    Article  Google Scholar 

  • Amiri Z, Weizman R, Katz Y, Burstein O, Edoute Y, Lochner A, Gavish M (1991) Testosterone and cyproterone acetate modulate peripheral but not central benzodiazepine receptors in rats. Brain Res 553:155–158

    Article  Google Scholar 

  • Anholt RR, Murphy KM, Mack GE, Snyder SH (1984) Peripheral-type benzodiazepine receptors in the central nervous system: localization to olfactory nerves. J Neurosci Off J Soc Neurosci 4:593–603

    Google Scholar 

  • Anholt RR, De Souza EB, Oster-Granite ML, Snyder SH (1985) Peripheral-type benzodiazepine receptors: autoradiographic localization in whole-body sections of neonatal rats. J Pharmacol Exp Ther 233:517–526

    Google Scholar 

  • Anholt RR, Pedersen PL, De Souza EB, Snyder SH (1986) The peripheral-type benzodiazepine receptor. Localization to the mitochondrial outer membrane. J Biol Chem 261:576–583

    Google Scholar 

  • Austin CJD, Kahlert J, Kassiou M, Rendina LM (2013) The translocator protein (TSPO): a novel target for cancer chemotherapy. Int J Biochem Cell Biol 45:1212–1216

    Article  Google Scholar 

  • Bae K-R, Shim H-J, Balu D, Kim SR, Yu S-W (2014) Translocator protein 18 kDa negatively regulates inflammation in microglia. J Neuroimmune Pharmacol Off J Soc NeuroImmune Pharmacol 9:424–437

    Article  Google Scholar 

  • Banati RB (2002) Visualising microglial activation in vivo. Glia 40:206–217

    Article  Google Scholar 

  • Banati RB, Middleton RJ, Chan R, Hatty CR, Kam WW-Y, Quin C, Graeber MB, Parmar A, Zahra D, Callaghan P et al (2014) Positron emission tomography and functional characterization of a complete PBR/TSPO knockout. Nat Commun 5:5452

    Article  Google Scholar 

  • Bar-Ami S, Fares F, Gavish M (1989) Effect of hypophysectomy and hormone treatment on the induction of peripheral-type benzodiazepine binding sites in female rat genital axis. Horm Metab Res Horm Stoffwechselforschung Horm Métabolisme 21:106–107

    Article  Google Scholar 

  • Batarseh A, Giatzakis C, Papadopoulos V (2008) Phorbol-12-myristate 13-acetate acting through protein kinase Cepsilon induces translocator protein (18-kDa) TSPO gene expression. Biochemistry (Mosc) 47:12886–12899

    Article  Google Scholar 

  • Batarseh A, Li J, Papadopoulos V (2010) Protein kinase C epsilon regulation of translocator protein (18 kDa) Tspo gene expression is mediated through a MAPK pathway targeting STAT3 and c-Jun transcription factors. Biochemistry (Mosc) 49:4766–4778

    Article  Google Scholar 

  • Batarseh A, Barlow KD, Martinez-Arguelles DB, Papadopoulos V (2012) Functional characterization of the human translocator protein (18kDa) gene promoter in human breast cancer cell lines. Biochim Biophys Acta 1819:38–56

    Article  Google Scholar 

  • Batra S, Iosif CS (2000) Peripheral benzodiazepine receptor in human endometrium and endometrial carcinoma. Anticancer Res 20:463–466

    Google Scholar 

  • Bedard K, Krause K-H (2007) The NOX family of ROS-generating NADPH oxidases: physiology and pathophysiology. Physiol Rev 87:245–313

    Article  Google Scholar 

  • Benavides J, Malgouris C, Imbault F, Begassat F, Uzan A, Renault C, Dubroeucq MC, Gueremy C, Le Fur G (1983a) “Peripheral type” benzodiazepine binding sites in rat adrenals: binding studies with [3H]PK 11195 and autoradiographic localization. Arch Int Pharmacodyn Thérapie 266:38–49

    Google Scholar 

  • Benavides J, Quarteronet D, Imbault F, Malgouris C, Uzan A, Renault C, Dubroeucq MC, Gueremy C, Le Fur G (1983b) Labelling of “peripheral-type” benzodiazepine binding sites in the rat brain by using [3H]PK 11195, an isoquinoline carboxamide derivative: kinetic studies and autoradiographic localization. J Neurochem 41:1744–1750

    Article  Google Scholar 

  • Benavides J, Menager J, Burgevin MC, Ferris O, Uzan A, Gueremy C, Renault C, Le Fur G (1985) Characterization of solubilized “peripheral type” benzodiazepine binding sites from rat adrenals by using [3H]PK 11195, an isoquinoline carboxamide derivative. Biochem Pharmacol 34:167–170

    Article  Google Scholar 

  • Benavides J, Fage D, Carter C, Scatton B (1987) Peripheral type benzodiazepine binding sites are a sensitive indirect index of neuronal damage. Brain Res 421:167–172

    Article  Google Scholar 

  • Bernassau JM, Reversat JL, Ferrara P, Caput D, Lefur G (1993) A 3D model of the peripheral benzodiazepine receptor and its implication in intra mitochondrial cholesterol transport. J Mol Graph 11(236–244):235

    Google Scholar 

  • Besman MJ, Yanagibashi K, Lee TD, Kawamura M, Hall PF, Shively JE (1989) Identification of des-(Gly-Ile)-endozepine as an effector of corticotropin-dependent adrenal steroidogenesis: stimulation of cholesterol delivery is mediated by the peripheral benzodiazepine receptor. Proc Natl Acad Sci U S A 86:4897–4901

    Article  ADS  Google Scholar 

  • Bitran D, Carlson D, Leschiner S, Gavish M (1998) Ovarian steroids and stress produce changes in peripheral benzodiazepine receptor density. Eur J Pharmacol 361:235–242

    Article  Google Scholar 

  • Blahos J, Whalin ME, Krueger KE (1995) Identification and purification of a 10-kilodalton protein associated with mitochondrial benzodiazepine receptors. J Biol Chem 270:20285–20291

    Article  Google Scholar 

  • Bloomer JR (1998) Liver metabolism of porphyrins and haem. J Gastroenterol Hepatol 13:324–329

    Article  Google Scholar 

  • Boujrad N, Gaillard JL, Garnier M, Papadopoulos V (1994) Acute action of choriogonadotropin on Leydig tumor cells: induction of a higher affinity benzodiazepine-binding site related to steroid biosynthesis. Endocrinology 135:1576–1583

    Article  Google Scholar 

  • Braestrup C, Squires RF (1977) Specific benzodiazepine receptors in rat brain characterized by high-affinity (3H)diazepam binding. Proc Natl Acad Sci U S A 74:3805–3809

    Article  ADS  Google Scholar 

  • Braestrup C, Albrechtsen R, Squires RF (1977) High densities of benzodiazepine receptors in human cortical areas. Nature 269:702–704

    Article  ADS  Google Scholar 

  • Cagnin A, Kassiou M, Meikle SR, Banati RB (2007) Positron emission tomography imaging of neuroinflammation. Neurother J Am Soc Exp Neurother 4:443–452

    Article  Google Scholar 

  • Calogero AE, Kamilaris TC, Bernardini R, Johnson EO, Chrousos GP, Gold PW (1990) Effects of peripheral benzodiazepine receptor ligands on hypothalamic-pituitary-adrenal axis function in the rat. J Pharmacol Exp Ther 253:729–737

    Google Scholar 

  • Campanella M, Szabadkai G, Rizzuto R (2008) Modulation of intracellular Ca2+ signalling in HeLa cells by the apoptotic cell death enhancer PK11195. Biochem Pharmacol 76:1628–1636

    Article  Google Scholar 

  • Carayon P, Portier M, Dussossoy D, Bord A, Petitprêtre G, Canat X, Le Fur G, Casellas P (1996) Involvement of peripheral benzodiazepine receptors in the protection of hematopoietic cells against oxygen radical damage. Blood 87:3170–3178

    Google Scholar 

  • Chelli B, Falleni A, Salvetti F, Gremigni V, Lucacchini A, Martini C (2001) Peripheral-type benzodiazepine receptor ligands: mitochondrial permeability transition induction in rat cardiac tissue. Biochem Pharmacol 61:695–705

    Article  Google Scholar 

  • Chen C, Kuo J, Wong A, Micevych P (2014) Estradiol modulates translocator protein (TSPO) and steroid acute regulatory protein (StAR) via protein kinase A (PKA) signaling in hypothalamic astrocytes. Endocrinology 155:2976–2985

    Article  Google Scholar 

  • Clark IE, Dodson MW, Jiang C, Cao JH, Huh JR, Seol JH, Yoo SJ, Hay BA, Guo M (2006) Drosophila pink1 is required for mitochondrial function and interacts genetically with parkin. Nature 441:1162–1166

    Article  ADS  Google Scholar 

  • Colasanti A, Owen DR, Grozeva D, Rabiner EA, Matthews PM, Craddock N, Young AH (2013) Bipolar disorder is associated with the rs6971 polymorphism in the gene encoding 18 kDa translocator protein (TSPO). Psychoneuroendocrinology 38:2826–2829

    Article  Google Scholar 

  • Cosenza-Nashat M, Zhao M-L, Suh H-S, Morgan J, Natividad R, Morgello S, Lee SC (2009) Expression of the translocator protein of 18 kDa by microglia, macrophages and astrocytes based on immunohistochemical localization in abnormal human brain. Neuropathol Appl Neurobiol 35:306–328

    Article  Google Scholar 

  • Costa B, Pini S, Gabelloni P, Da Pozzo E, Abelli M, Lari L, Preve M, Lucacchini A, Cassano GB, Martini C (2009a) The spontaneous Ala147Thr amino acid substitution within the translocator protein influences pregnenolone production in lymphomonocytes of healthy individuals. Endocrinology 150:5438–5445

    Article  Google Scholar 

  • Costa B, Pini S, Martini C, Abelli M, Gabelloni P, Landi S, Muti M, Gesi C, Lari L, Cardini A et al (2009b) Ala147Thr substitution in translocator protein is associated with adult separation anxiety in patients with depression. Psychiatr Genet 19:110–111

    Article  Google Scholar 

  • Court FA, Coleman MP (2012) Mitochondria as a central sensor for axonal degenerative stimuli. Trends Neurosci 35:364–372

    Article  Google Scholar 

  • Da Pozzo E, Giacomelli C, Barresi E, Costa B, Taliani S, Passetti FDS, Martini C (2015) Targeting the 18-kDa translocator protein: recent perspectives for neuroprotection. Biochem Soc Trans 43:559–565

    Article  Google Scholar 

  • De Souza EB, Anholt RR, Murphy KM, Snyder SH, Kuhar MJ (1985) Peripheral-type benzodiazepine receptors in endocrine organs: autoradiographic localization in rat pituitary, adrenal, and testis. Endocrinology 116:567–573

    Article  Google Scholar 

  • Delavoie F, Li H, Hardwick M, Robert J-C, Giatzakis C, Péranzi G, Yao Z-X, Maccario J, Lacapère J-J, Papadopoulos V (2003) In vivo and in vitro peripheral-type benzodiazepine receptor polymerization: functional significance in drug ligand and cholesterol binding. Biochemistry (Mosc) 42:4506–4519

    Article  Google Scholar 

  • Dias V, Junn E, Mouradian MM (2013) The role of oxidative stress in Parkinson’s disease. J Park Dis 3:461–491

    Google Scholar 

  • Dias IHK, Mistry J, Fell S, Reis A, Spickett CM, Polidori MC, Lip GYH, Griffiths HR (2014) Oxidized LDL lipids increase ?-amyloid production by SH-SY5Y cells through glutathione depletion and lipid raft formation. Free Radic Biol Med 75:48–59

    Article  Google Scholar 

  • Dröge W (2002) Free radicals in the physiological control of cell function. Physiol Rev 82:47–95

    Article  Google Scholar 

  • Dubois A, Bénavidès J, Peny B, Duverger D, Fage D, Gotti B, MacKenzie ET, Scatton B (1988) Imaging of primary and remote ischaemic and excitotoxic brain lesions. An autoradiographic study of peripheral type benzodiazepine binding sites in the rat and cat. Brain Res 445:77–90

    Article  Google Scholar 

  • Fan J, Papadopoulos V (2012) Transcriptional regulation of translocator protein (Tspo) via a SINE B2-mediated natural antisense transcript in MA-10 Leydig cells. Biol Reprod 86:147

    Article  Google Scholar 

  • Fan J, Rone MB, Papadopoulos V (2009) Translocator protein 2 is involved in cholesterol redistribution during erythropoiesis. J Biol Chem 284:30484–30497

    Article  Google Scholar 

  • Fan J, Liu J, Culty M, Papadopoulos V (2010) Acyl-coenzyme A binding domain containing 3 (ACBD3; PAP7; GCP60): an emerging signaling molecule. Prog Lipid Res 49:218–234

    Article  Google Scholar 

  • Fan J, Campioli E, Midzak A, Culty M, Papadopoulos V (2015) Conditional steroidogenic cell-targeted deletion of TSPO unveils a crucial role in viability and hormone-dependent steroid formation. Proc Natl Acad Sci U S A 112:7261–7266

    Article  ADS  Google Scholar 

  • Fantini J, Di Scala C, Evans LS, Williamson PTF, Barrantes FJ (2016) A mirror code for protein-cholesterol interactions in the two leaflets of biological membranes. Sci Rep 6:213–222

    Article  Google Scholar 

  • Fares F, Bar-Ami S, Brandes JM, Gavish M (1987) Gonadotropin- and estrogen-induced increase of peripheral-type benzodiazepine binding sites in the hypophyseal-genital axis of rats. Eur J Pharmacol 133:97–102

    Article  Google Scholar 

  • Fares F, Bar-Ami S, Brandes JM, Gavish M (1988) Changes in the density of peripheral benzodiazepine binding sites in genital organs of the female rat during the oestrous cycle. J Reprod Fertil 83:619–625

    Article  Google Scholar 

  • Farges R, Joseph-Liauzun E, Shire D, Caput D, Fur GL, Ferrara P (1994) Site-directed mutagenesis of the peripheral benzodiazepine receptor: identification of amino acids implicated in the binding site of Ro5-4864. Mol Pharmacol 46:1160–1167

    Google Scholar 

  • Fay J, Varoga D, Wruck CJ, Kurz B, Goldring MB, Pufe T (2006) Reactive oxygen species induce expression of vascular endothelial growth factor in chondrocytes and human articular cartilage explants. Arthritis Res Ther 8:R189

    Article  Google Scholar 

  • Frank W, Baar K-M, Qudeimat E, Woriedh M, Alawady A, Ratnadewi D, Gremillon L, Grimm B, Reski R (2007) A mitochondrial protein homologous to the mammalian peripheral-type benzodiazepine receptor is essential for stress adaptation in plants. Plant J 51:1004–1018

    Article  Google Scholar 

  • Galiègue S, Casellas P, Kramar A, Tinel N, Simony-Lafontaine J (2004) Immunohistochemical assessment of the peripheral benzodiazepine receptor in breast cancer and its relationship with survival. Clin Cancer Res Off J Am Assoc Cancer Res 10:2058–2064

    Article  Google Scholar 

  • Garnier M, Dimchev AB, Boujrad N, Price JM, Musto NA, Papadopoulos V (1994) In vitro reconstitution of a functional peripheral-type benzodiazepine receptor from mouse Leydig tumor cells. Mol Pharmacol 45:201–211

    Google Scholar 

  • Gatliff J, Campanella M (2015) TSPO is a REDOX regulator of cell mitophagy. Biochem Soc Trans 43:543–552

    Article  Google Scholar 

  • Gatliff J, Campanella M (2016) TSPO: kaleidoscopic 18-kDa amid biochemical pharmacology, control and targeting of mitochondria. Biochem J 473:107–121

    Article  Google Scholar 

  • Gatliff J, East D, Crosby J, Abeti R, Harvey R, Craigen W, Parker P, Campanella M (2014) TSPO interacts with VDAC1 and triggers a ROS-mediated inhibition of mitochondrial quality control. Autophagy 10(12):2279–2296. doi: 10.4161/15548627.2014.991665.

  • Gautier CA, Kitada T, Shen J (2008) Loss of PINK1 causes mitochondrial functional defects and increased sensitivity to oxidative stress. Proc Natl Acad Sci U S A 105:11364–11369

    Article  ADS  Google Scholar 

  • Gavish M, Bachman I, Shoukrun R, Katz Y, Veenman L, Weisinger G, Weizman A (1999) Enigma of the peripheral benzodiazepine receptor. Pharmacol Rev 51:629–650

    Google Scholar 

  • Gazouli M, Yao Z-X, Boujrad N, Corton JC, Culty M, Papadopoulos V (2002) Effect of peroxisome proliferators on Leydig cell peripheral-type benzodiazepine receptor gene expression, hormone-stimulated cholesterol transport, and steroidogenesis: role of the peroxisome proliferator-activator receptor alpha. Endocrinology 143:2571–2583

    Article  Google Scholar 

  • Ghosh N, Ghosh R, Mandal SC (2011) Antioxidant protection: a promising therapeutic intervention in neurodegenerative disease. Free Radic Res 45:888–905

    Article  Google Scholar 

  • Giatzakis C, Papadopoulos V (2004) Differential utilization of the promoter of peripheral-type benzodiazepine receptor by steroidogenic versus nonsteroidogenic cell lines and the role of Sp1 and Sp3 in the regulation of basal activity. Endocrinology 145:1113–1123

    Article  Google Scholar 

  • Giatzakis C, Batarseh A, Dettin L, Papadopoulos V (2007) The role of Ets transcription factors in the basal transcription of the translocator protein (18 kDa). Biochemistry (Mosc) 46:4763–4774

    Article  Google Scholar 

  • Ginter C, Kiburu I, Boudker O (2013) Chemical catalysis by the translocator protein (18 kDa). Biochemistry (Mosc) 52:3609–3611

    Article  Google Scholar 

  • Giorgio V, von Stockum S, Antoniel M, Fabbro A, Fogolari F, Forte M, Glick GD, Petronilli V, Zoratti M, Szabó I et al (2013) Dimers of mitochondrial ATP synthase form the permeability transition pore. Proc Natl Acad Sci 110:5887–5892

    Article  ADS  Google Scholar 

  • Gomez-Nicola D, Perry VH (2015) Microglial dynamics and role in the healthy and diseased brain: a paradigm of functional plasticity. Neuroscientist 21(2):169–184.

    Google Scholar 

  • Gonzalez-Polo R-A, Carvalho G, Braun T, Decaudin D, Fabre C, Larochette N, Perfettini J-L, Djavaheri-Mergny M, Youlyouz-Marfak I, Codogno P et al (2005) PK11195 potently sensitizes to apoptosis induction independently from the peripheral benzodiazepin receptor. Oncogene 24:7503–7513

    Article  Google Scholar 

  • Graeber MB (2010) Changing face of microglia. Science 330:783–788

    Article  ADS  Google Scholar 

  • Gray PW, Glaister D, Seeburg PH, Guidotti A, Costa E (1986) Cloning and expression of cDNA for human diazepam binding inhibitor, a natural ligand of an allosteric regulatory site of the gamma-aminobutyric acid type A receptor. Proc Natl Acad Sci U S A 83:7547–7551

    Article  ADS  Google Scholar 

  • Guidotti A, Forchetti CM, Corda MG, Konkel D, Bennett CD, Costa E (1983) Isolation, characterization, and purification to homogeneity of an endogenous polypeptide with agonistic action on benzodiazepine receptors. Proc Natl Acad Sci U S A 80:3531–3535

    Article  ADS  Google Scholar 

  • Guo Y, Kalathur RC, Liu Q, Kloss B, Bruni R, Ginter C, Kloppmann E, Rost B, Hendrickson WA (2015) Structure and activity of tryptophan-rich TSPO proteins. Science 347:551–555

    Article  ADS  Google Scholar 

  • Gut P, Baeza-Raja B, Andersson O, Hasenkamp L, Hsiao J, Hesselson D, Akassoglou K, Verdin E, Hirschey MD, Stainier DYR (2013) Whole-organism screening for gluconeogenesis identifies activators of fasting metabolism. Nat Chem Biol 9:97–104

    Article  Google Scholar 

  • Gut P, Zweckstetter M, Banati RB (2015) Lost in translocation: the functions of the 18-kD translocator protein. Trends Endocrinol Metab TEM 26:349–356

    Article  Google Scholar 

  • Halestrap AP (2009) What is the mitochondrial permeability transition pore? J Mol Cell Cardiol 46:821–831

    Article  Google Scholar 

  • Handschin C, Lin J, Rhee J, Peyer A-K, Chin S, Wu P-H, Meyer UA, Spiegelman BM (2005) Nutritional regulation of hepatic heme biosynthesis and porphyria through PGC-1α. Cell 122:505–515

    Article  Google Scholar 

  • Hardwick M, Fertikh D, Culty M, Li H, Vidic B, Papadopoulos V (1999) Peripheral-type benzodiazepine receptor (PBR) in human breast cancer. Cancer Res 59:831–842

    Google Scholar 

  • Harrison R (2002) Structure and function of xanthine oxidoreductase: where are we now? Free Radic Biol Med 33:774–797

    Article  Google Scholar 

  • Hirsch T, Decaudin D, Susin SA, Marchetti P, Larochette N, Resche-Rigon M, Kroemer G (1998) PK11195, a ligand of the mitochondrial benzodiazepine receptor, facilitates the induction of apoptosis and reverses Bcl-2-mediated cytoprotection. Exp Cell Res 241:426–434

    Article  Google Scholar 

  • Huang R, Zhao L, Chen H, Yin R-H, Li C-Y, Zhan Y-Q, Zhang J-H, Ge C, Yu M, Yang X-M (2014) Megakaryocytic differentiation of K562 cells induced by PMA reduced the activity of respiratory chain complex IV. PLoS One 9:e96246

    Article  ADS  Google Scholar 

  • Janczar K, Su Z, Raccagni I, Anfosso A, Kelly C, Durrenberger PF, Gerhard A, Roncaroli F (2015) The 18-kDa mitochondrial translocator protein in gliomas: from the bench to bedside. Biochem Soc Trans 43:579–585

    Article  Google Scholar 

  • Jaremko L, Jaremko M, Giller K, Becker S, Zweckstetter M (2014) Structure of the mitochondrial translocator protein in complex with a diagnostic ligand. Science 343:1363–1366

    Article  ADS  Google Scholar 

  • Jaremko Ł, Jaremko M, Giller K, Becker S, Zweckstetter M (2015a) Conformational flexibility in the transmembrane protein TSPO. Chem Weinh Bergstr Ger 21:16555–16563

    Google Scholar 

  • Jaremko M, Jaremko Ł, Giller K, Becker S, Zweckstetter M (2015b) Structural integrity of the A147T polymorph of mammalian TSPO. Chembiochem Eur J Chem Biol 16:1483–1489

    Article  Google Scholar 

  • Jayakumar AR, Panickar KS, Norenberg MD (2002) Effects on free radical generation by ligands of the peripheral benzodiazepine receptor in cultured neural cells. J Neurochem 83:1226–1234

    Article  Google Scholar 

  • Jordà EG, Jiménez A, Verdaguer E, Canudas AM, Folch J, Sureda FX, Camins A, Pallàs M (2005) Evidence in favour of a role for peripheral-type benzodiazepine receptor ligands in amplification of neuronal apoptosis. Apoptosis Int J Program Cell Death 10:91–104

    Article  Google Scholar 

  • Joseph-Liauzun E, Delmas P, Shire D, Ferrara P (1998) Topological analysis of the peripheral benzodiazepine receptor in yeast mitochondrial membranes supports a five-transmembrane structure. J Biol Chem 273:2146–2152

    Article  Google Scholar 

  • Junck L, Olson JM, Ciliax BJ, Koeppe RA, Watkins GL, Jewett DM, McKeever PE, Wieland DM, Kilbourn MR, Starosta-Rubinstein S (1989) PET imaging of human gliomas with ligands for the peripheral benzodiazepine binding site. Ann Neurol 26:752–758

    Article  Google Scholar 

  • Karchewski LA, Bloechlinger S, Woolf CJ (2004) Axonal injury-dependent induction of the peripheral benzodiazepine receptor in small-diameter adult rat primary sensory neurons. Eur J Neurosci 20:671–683

    Article  Google Scholar 

  • Karlstetter M, Nothdurfter C, Aslanidis A, Moeller K, Horn F, Scholz R, Neumann H, Weber BHF, Rupprecht R, Langmann T (2014) Translocator protein (18 kDa) (TSPO) is expressed in reactive retinal microglia and modulates microglial inflammation and phagocytosis. J Neuroinflammation 11:3

    Article  Google Scholar 

  • Keshari RS, Verma A, Barthwal MK, Dikshit M (2013) Reactive oxygen species-induced activation of ERK and p38 MAPK mediates PMA-induced NETs release from human neutrophils. J Cell Biochem 114:532–540

    Article  Google Scholar 

  • Kokoszka JE, Waymire KG, Levy SE, Sligh JE, Cai J, Jones DP, MacGregor GR, Wallace DC (2004) The ADP/ATP translocator is not essential for the mitochondrial permeability transition pore. Nature 427:461–465

    Article  ADS  Google Scholar 

  • Kruczek C, Görg B, Keitel V, Pirev E, Kröncke KD, Schliess F, Häussinger D (2009) Hypoosmotic swelling affects zinc homeostasis in cultured rat astrocytes. Glia 57:79–92

    Article  Google Scholar 

  • Krueger KE, Papadopoulos V (1990) Peripheral-type benzodiazepine receptors mediate translocation of cholesterol from outer to inner mitochondrial membranes in adrenocortical cells. J Biol Chem 265:15015–15022

    Google Scholar 

  • Lacapère JJ, Delavoie F, Li H, Péranzi G, Maccario J, Papadopoulos V, Vidic B (2001) Structural and functional study of reconstituted peripheral benzodiazepine receptor. Biochem Biophys Res Commun 284:536–541

    Article  Google Scholar 

  • Lazarou M, Sliter DA, Kane LA, Sarraf SA, Wang C, Burman JL, Sideris DP, Fogel AI, Youle RJ (2015) The ubiquitin kinase PINK1 recruits autophagy receptors to induce mitophagy. Nature 524:309–314

    Article  ADS  Google Scholar 

  • Lee D-H, Steinacker P, Seubert S, Turnescu T, Melms A, Manzel A, Otto M, Linker RA (2015) Role of glial 14-3-3 gamma protein in autoimmune demyelination. J Neuroinflammation 12:187

    Article  Google Scholar 

  • Lee J-W, Kim LE, Shim H-J, Kim E-K, Hwang WC, Min DS, Yu S-W (2016) A translocator protein 18 kDa ligand, Ro5-4864, inhibits ATP-induced NLRP3 inflammasome activation. Biochem Biophys Res Commun 474:587–593

    Article  Google Scholar 

  • Lehtonen MT, Akita M, Frank W, Reski R, Valkonen JPT (2012) Involvement of a class III peroxidase and the mitochondrial protein TSPO in oxidative burst upon treatment of moss plants with a fungal elicitor. Mol Plant-Microbe Interact MPMI 25:363–371

    Article  Google Scholar 

  • Lemasters JJ (2005) Selective mitochondrial autophagy, or mitophagy, as a targeted defense against oxidative stress, mitochondrial dysfunction, and aging. Rejuvenation Res 8:3–5

    Article  Google Scholar 

  • Lemasters JJ, Holmuhamedov E (2006) Voltage-dependent anion channel (VDAC) as mitochondrial governator – thinking outside the box. Biochim Biophys Acta 1762:181–190

    Article  Google Scholar 

  • Li H, Papadopoulos V (1998) Peripheral-type benzodiazepine receptor function in cholesterol transport. Identification of a putative cholesterol recognition/interaction amino acid sequence and consensus pattern. Endocrinology 139:4991–4997

    Article  Google Scholar 

  • Li J, Papadopoulos V (2015) Translocator protein (18 kDa) as a pharmacological target in adipocytes to regulate glucose homeostasis. Biochem Pharmacol 97:99–110

    Article  Google Scholar 

  • Li H, Degenhardt B, Tobin D, Yao ZX, Tasken K, Papadopoulos V (2001) Identification, localization, and function in steroidogenesis of PAP7: a peripheral-type benzodiazepine receptor- and PKA (RIalpha)-associated protein. Mol Endocrinol Baltim Md 15:2211–2228

    Google Scholar 

  • Li F, Liu J, Valls L, Hiser C, Ferguson-Miller S (2015a) Identification of a key cholesterol binding enhancement motif in translocator protein 18 kDa. Biochemistry (Mosc) 54:1441–1443

    Article  Google Scholar 

  • Li F, Liu J, Zheng Y, Garavito RM, Ferguson-Miller S (2015b) Crystal structures of translocator protein (TSPO) and mutant mimic of a human polymorphism. Science 347:555–558

    Article  ADS  Google Scholar 

  • Lin R, Angelin A, Da Settimo F, Martini C, Taliani S, Zhu S, Wallace DC (2014) Genetic analysis of dTSPO, an outer mitochondrial membrane protein, reveals its functions in apoptosis, longevity, and Ab42-induced neurodegeneration. Aging Cell 13:507–518

    Article  Google Scholar 

  • Liu J, Rone MB, Papadopoulos V (2006) Protein-protein interactions mediate mitochondrial cholesterol transport and steroid biosynthesis. J Biol Chem 281:38879–38893

    Article  Google Scholar 

  • Maldonado EN, Lemasters JJ (2012) Warburg revisited: regulation of mitochondrial metabolism by voltage-dependent anion channels in cancer cells. J Pharmacol Exp Ther 342:637–641

    Article  Google Scholar 

  • Matic I, Strobbe D, Frison M, Campanella M (2015) Controlled and impaired mitochondrial quality in neurons: molecular physiology and prospective pharmacology. Pharmacol Res Off J Ital Pharmacol Soc

    Google Scholar 

  • Mazurika C, Veenman L, Weizman R, Bidder M, Leschiner S, Golani I, Spanier I, Weisinger G, Gavish M (2009) Estradiol modulates uterine 18 kDa translocator protein gene expression in uterus and kidney of rats. Mol Cell Endocrinol 307:43–49

    Article  Google Scholar 

  • McEnery MW, Snowman AM, Trifiletti RR, Snyder SH (1992) Isolation of the mitochondrial benzodiazepine receptor: association with the voltage-dependent anion channel and the adenine nucleotide carrier. Proc Natl Acad Sci U S A 89:3170–3174

    Article  ADS  Google Scholar 

  • Medzhitov R (2008) Origin and physiological roles of inflammation. Nature 454:428–435

    Article  ADS  Google Scholar 

  • Mercer KA, Weizman R, Gavish M (1992) Ontogenesis of peripheral benzodiazepine receptors: demonstration of selective up-regulation in rat testis as a function of maturation. J Recept Res 12:413–425

    Article  Google Scholar 

  • Midzak A, Zirkin B, Papadopoulos V (2015) Translocator protein: pharmacology and steroidogenesis. Biochem Soc Trans 43:572–578

    Article  Google Scholar 

  • Miller WL, Auchus RJ (2011) The molecular biology, biochemistry, and physiology of human steroidogenesis and its disorders. Endocr Rev 32:81–151

    Article  Google Scholar 

  • Morin D, Musman J, Pons S, Berdeaux A, Ghaleh B (2016) Mitochondrial translocator protein (TSPO): from physiology to cardioprotection. Biochem Pharmacol 105:1–13

    Article  Google Scholar 

  • Murail S, Robert J-C, Coïc Y-M, Neumann J-M, Ostuni MA, Yao Z-X, Papadopoulos V, Jamin N, Lacapère J-J (2008) Secondary and tertiary structures of the transmembrane domains of the translocator protein TSPO determined by NMR. Stabilization of the TSPO tertiary fold upon ligand binding. Biochim Biophys Acta 1778:1375–1381

    Article  Google Scholar 

  • Murphy MP (2009) How mitochondria produce reactive oxygen species. Biochem J 417:1–13

    Article  Google Scholar 

  • Naegele M, Martin R (2014) The good and the bad of neuroinflammation in multiple sclerosis. Handb Clin Neurol 122:59–87

    Article  Google Scholar 

  • Nakazawa F, Alev C, Shin M, Nakaya Y, Jakt LM, Sheng G (2009) PBRL, a putative peripheral benzodiazepine receptor, in primitive erythropoiesis. Gene Expr Patterns GEP 9:114–121

    Article  Google Scholar 

  • Olson JMM, Ciliax BJ, Mancini WR, Young AB (1988) Presence of peripheral-type benzodiazepine binding sites on human erythrocyte membranes. Eur J Pharmacol 152:47–53

    Article  Google Scholar 

  • Owen DRJ, Lewis AJM, Reynolds R, Rupprecht R, Eser D, Wilkins MR, Bennacef I, Nutt DJ, Parker CA (2011) Variation in binding affinity of the novel anxiolytic XBD173 for the 18 kDa translocator protein in human brain. Synap N Y N 65:257–259

    Article  Google Scholar 

  • Owen DR, Yeo AJ, Gunn RN, Song K, Wadsworth G, Lewis A, Rhodes C, Pulford DJ, Bennacef I, Parker CA et al (2012) An 18-kDa translocator protein (TSPO) polymorphism explains differences in binding affinity of the PET radioligand PBR28. J Cereb Blood Flow Metab Off J Int Soc Cereb Blood Flow Metab 32:1–5

    Article  Google Scholar 

  • Palzur E, Sharon A, Shehadeh M, Soustiel JF (2016) Investigation of the mechanisms of neuroprotection mediated by Ro5-4864 in brain injury. Neuroscience 329:162–170

    Article  Google Scholar 

  • Pandey D, Gratton J-P, Rafikov R, Black SM, Fulton DJR (2011) Calcium/calmodulin-dependent kinase II mediates the phosphorylation and activation of NADPH oxidase 5. Mol Pharmacol 80:407–415

    Article  Google Scholar 

  • Papadopoulos V, Mukhin AG, Costa E, Krueger KE (1990) The peripheral-type benzodiazepine receptor is functionally linked to Leydig cell steroidogenesis. J Biol Chem 265:3772–3779

    Google Scholar 

  • Papadopoulos V, Berkovich A, Krueger KE, Costa E, Guidotti A (1991) Diazepam binding inhibitor and its processing products stimulate mitochondrial steroid biosynthesis via an interaction with mitochondrial benzodiazepine receptors. Endocrinology 129:1481–1488

    Article  Google Scholar 

  • Papadopoulos V, Boujrad N, Ikonomovic MD, Ferrara P, Vidic B (1994) Topography of the Leydig cell mitochondrial peripheral-type benzodiazepine receptor. Mol Cell Endocrinol 104:R5–R9

    Article  Google Scholar 

  • Papadopoulos V, Amri H, Boujrad N, Cascio C, Culty M, Garnier M, Hardwick M, Li H, Vidic B, Brown AS et al (1997a) Peripheral benzodiazepine receptor in cholesterol transport and steroidogenesis. Steroids 62:21–28

    Article  Google Scholar 

  • Papadopoulos V, Amri H, Li H, Boujrad N, Vidic B, Garnier M (1997b) Targeted disruption of the peripheral-type benzodiazepine receptor gene inhibits steroidogenesis in the R2C Leydig tumor cell line. J Biol Chem 272:32129–32135

    Article  Google Scholar 

  • Papadopoulos V, Baraldi M, Guilarte TR, Knudsen TB, Lacapère J-J, Lindemann P, Norenberg MD, Nutt D, Weizman A, Zhang M-R et al (2006) Translocator protein (18kDa): new nomenclature for the peripheral-type benzodiazepine receptor based on its structure and molecular function. Trends Pharmacol Sci 27:402–409

    Article  Google Scholar 

  • Ponka P (1999) Cell biology of heme. Am J Med Sci 318:241–256

    Article  Google Scholar 

  • Puigserver P, Rhee J, Donovan J, Walkey CJ, Yoon JC, Oriente F, Kitamura Y, Altomonte J, Dong H, Accili D et al (2003) Insulin-regulated hepatic gluconeogenesis through FOXO1–PGC-1α interaction. Nature 423:550–555

    Article  ADS  Google Scholar 

  • Qi X, Xu J, Wang F, Xiao J (2012) Translocator protein (18 kDa): a promising therapeutic target and diagnostic tool for cardiovascular diseases. Oxid Med Cell Longev 2012:162934

    Article  Google Scholar 

  • Rampon C, Bouzaffour M, Ostuni MA, Dufourcq P, Girard C, Freyssinet JM, Lacapere J-J, Schweizer-Groyer G, Vriz S (2009) Translocator protein (18 kDa) is involved in primitive erythropoiesis in zebrafish. FASEB J Off Publ Fed Am Soc Exp Biol 23:4181–4192

    Google Scholar 

  • Randow F, Youle RJ (2014) Self and nonself: how autophagy targets mitochondria and bacteria. Cell Host Microbe 15:403–411

    Article  Google Scholar 

  • Ransohoff RM, Perry VH (2009) Microglial physiology: unique stimuli, specialized responses. Annu Rev Immunol 27:119–145

    Article  Google Scholar 

  • Rechichi M, Salvetti A, Chelli B, Costa B, Da Pozzo E, Spinetti F, Lena A, Evangelista M, Rainaldi G, Martini C et al (2008) TSPO over-expression increases motility, transmigration and proliferation properties of C6 rat glioma cells. Biochim Biophys Acta 1782:118–125

    Article  Google Scholar 

  • Rizzuto R, De Stefani D, Raffaello A, Mammucari C (2012) Mitochondria as sensors and regulators of calcium signalling. Nat Rev Mol Cell Biol 13:566–578

    Article  Google Scholar 

  • Rogers J, Mastroeni D, Leonard B, Joyce J, Grover A (2007) Neuroinflammation in Alzheimer’s disease and Parkinson’s disease: are microglia pathogenic in either disorder? Int Rev Neurobiol 82:235–246

    Article  Google Scholar 

  • Rone M, Liu J, Blonder J, Ye X, Veenstra TD, Young JC, Papadopoulos V (2009) Targeting and insertion of the cholesterol-binding translocator protein into the outer mitochondrial membrane. Biochemistry (Mosc) 48:6909–6920

    Article  Google Scholar 

  • Rosenberg N, Rosenberg O, Weizman A, Veenman L, Gavish M (2014) In vitro effect of FGIN-1-27, a ligand to 18 kDa mitochondrial translocator protein, in human osteoblast-like cells. J Bioenerg Biomembr 46:197–204

    Article  Google Scholar 

  • Rupprecht R, Rammes G, Eser D, Baghai TC, Schüle C, Nothdurfter C, Troxler T, Gentsch C, Kalkman HO, Chaperon F et al (2009) Translocator protein (18 kD) as target for anxiolytics without benzodiazepine-like side effects. Science 325:490–493

    Article  ADS  Google Scholar 

  • Rupprecht R, Papadopoulos V, Rammes G, Baghai TC, Fan J, Akula N, Groyer G, Adams D, Schumacher M (2010) Translocator protein (18 kDa) (TSPO) as a therapeutic target for neurological and psychiatric disorders. Nat Rev Drug Discov 9:971–988

    Article  Google Scholar 

  • Saari TI, Uusi-Oukari M, Ahonen J, Olkkola KT (2011) Enhancement of GABAergic activity: neuropharmacological effects of benzodiazepines and therapeutic use in anesthesiology. Pharmacol Rev 63:243–267

    Article  Google Scholar 

  • Selvaraj V, Stocco DM (2015) The changing landscape in translocator protein (TSPO) function. Trends Endocrinol Metab 26:341–348

    Article  Google Scholar 

  • Seneviratne MSD, Faccenda D, De Biase V, Campanella M (2012) PK11195 inhibits mitophagy targeting the F1Fo-ATPsynthase in Bcl-2 knock-down cells. Curr Mol Med 12:476–482

    Google Scholar 

  • Sheldon KL, Maldonado EN, Lemasters JJ, Rostovtseva TK, Bezrukov SM (2011) Phosphorylation of voltage-dependent anion channel by serine/threonine kinases governs its interaction with tubulin. PLoS One 6:e25539

    Article  ADS  Google Scholar 

  • Shoshan-Barmatz V, Ben-Hail D, Admoni L, Krelin Y, Tripathi SS (2015) The mitochondrial voltage-dependent anion channel 1 in tumor cells. Biochim Biophys Acta BBA – Biomembr 1848:2547–2575

    Article  Google Scholar 

  • Sileikyte J, Petronilli V, Zulian A, Dabbeni-Sala F, Tognon G, Nikolov P, Bernardi P, Ricchelli F (2011) Regulation of the inner membrane mitochondrial permeability transition by the outer membrane translocator protein (peripheral benzodiazepine receptor). J Biol Chem 286:1046–1053

    Article  Google Scholar 

  • Smith SM, Vale WW (2006) The role of the hypothalamic-pituitary-adrenal axis in neuroendocrine responses to stress. Dialogues Clin Neurosci 8:383–395

    Google Scholar 

  • Sutter AP, Maaser K, Höpfner M, Barthel B, Grabowski P, Faiss S, Carayon P, Zeitz M, Scherübl H (2002) Specific ligands of the peripheral benzodiazepine receptor induce apoptosis and cell cycle arrest in human esophageal cancer cells. Int J Cancer 102:318–327

    Article  Google Scholar 

  • Tamse CT, Lu X, Mortel EG, Cabrales E, Feng W, Schaefer S (2008) The peripheral benzodiazepine receptor modulates Ca2+ transport through the VDAC in rat heart mitochondria. J Clin Basic Cardiol 11(1-4):24–29

    Google Scholar 

  • Tanida I, Ueno T, Kominami E (2004) LC3 conjugation system in mammalian autophagy. Int J Biochem Cell Biol 36:2503–2518

    Article  Google Scholar 

  • Trincavelli ML, Marselli L, Falleni A, Gremigni V, Ragge E, Dotta F, Santangelo C, Marchetti P, Lucacchini A, Martini C (2002) Upregulation of mitochondrial peripheral benzodiazepine receptor expression by cytokine-induced damage of human pancreatic islets. J Cell Biochem 84:636–644

    Article  Google Scholar 

  • Tu LN, Morohaku K, Manna PR, Pelton SH, Butler WR, Stocco DM, Selvaraj V (2014) Peripheral benzodiazepine receptor/translocator protein global knock-out mice are viable with no effects on steroid hormone biosynthesis. J Biol Chem 289:27444–27454

    Article  Google Scholar 

  • Tu LN, Zhao AH, Stocco DM, Selvaraj V (2015) PK11195 effect on steroidogenesis is not mediated through the translocator protein (TSPO). Endocrinology 156:1033–1039

    Article  Google Scholar 

  • Tu LN, Zhao AH, Hussein M, Selvaraj V (2016) Mitochondrial translocator protein (TSPO) is a regulator of fatty acid metabolism. FASEB J 30:850.8–850.8

    Google Scholar 

  • Turkheimer FE, Rizzo G, Bloomfield PS, Howes O, Zanotti-Fregonara P, Bertoldo A, Veronese M (2015) The methodology of TSPO imaging with positron emission tomography. Biochem Soc Trans 43:586–592

    Article  Google Scholar 

  • Ujwal R, Cascio D, Colletier J-P, Faham S, Zhang J, Toro L, Ping P, Abramson J (2008) The crystal structure of mouse VDAC1 at 2.3 Å resolution reveals mechanistic insights into metabolite gating. Proc Natl Acad Sci 105:17742–17747

    Article  ADS  Google Scholar 

  • Vanhee C, Zapotoczny G, Masquelier D, Ghislain M, Batoko H (2011) The arabidopsis multistress regulator TSPO is a heme binding membrane protein and a potential scavenger of porphyrins via an autophagy-dependent degradation mechanism. Plant Cell 23:785–805

    Article  Google Scholar 

  • Varga B, Markó K, Hádinger N, Jelitai M, Demeter K, Tihanyi K, Vas A, Madarász E (2009) Translocator protein (TSPO 18kDa) is expressed by neural stem and neuronal precursor cells. Neurosci Lett 462:257–262

    Article  Google Scholar 

  • Veenman L, Gavish M (2006) The peripheral-type benzodiazepine receptor and the cardiovascular system. Implications for drug development. Pharmacol Ther 110:503–524

    Article  Google Scholar 

  • Veenman L, Levin E, Weisinger G, Leschiner S, Spanier I, Snyder SH, Weizman A, Gavish M (2004) Peripheral-type benzodiazepine receptor density and in vitro tumorigenicity of glioma cell lines. Biochem Pharmacol 68:689–698

    Article  Google Scholar 

  • Veenman L, Papadopoulos V, Gavish M (2007) Channel-like functions of the 18-kDa translocator protein (TSPO): regulation of apoptosis and steroidogenesis as part of the host-defense response. Curr Pharm Des 13:2385–2405

    Article  Google Scholar 

  • Veenman L, Gavish M, Kugler W (2014) Apoptosis induction by erucylphosphohomocholine via the 18 kDa mitochondrial translocator protein: implications for cancer treatment. Anticancer Agents Med Chem 14:559–577

    Article  Google Scholar 

  • Vega RB, Huss JM, Kelly DP (2000) The coactivator PGC-1 cooperates with peroxisome proliferator-activated receptor alpha in transcriptional control of nuclear genes encoding mitochondrial fatty acid oxidation enzymes. Mol Cell Biol 20:1868–1876

    Article  Google Scholar 

  • Verma A, Nye JS, Snyder SH (1987) Porphyrins are endogenous ligands for the mitochondrial (peripheral-type) benzodiazepine receptor. Proc Natl Acad Sci U S A 84:2256–2260

    Article  ADS  Google Scholar 

  • Weizman A, Amiri Z, Katz Y, Snyder SH, Gavish M (1992) Testosterone prevents castration-induced reduction in peripheral benzodiazepine receptors in Cowper’s gland and adrenal. Brain Res 572:72–75

    Article  Google Scholar 

  • Werry EL, Barron ML, Kassiou M (2015) TSPO as a target for glioblastoma therapeutics. Biochem Soc Trans 43:531–536

    Article  Google Scholar 

  • Wu Y, Kazumura K, Maruyama W, Osawa T, Naoi M (2015) Rasagiline and selegiline suppress calcium efflux from mitochondria by PK11195-induced opening of mitochondrial permeability transition pore: a novel anti-apoptotic function for neuroprotection. J Neural Transm Vienna Austria 122:1399–14071996

    Article  Google Scholar 

  • Yeliseev AA, Kaplan S (2000) TspO of rhodobacter sphaeroides. A structural and functional model for the mammalian peripheral benzodiazepine receptor. J Biol Chem 275:5657–5667

    Article  Google Scholar 

  • Yeliseev AA, Krueger KE, Kaplan S (1997) A mammalian mitochondrial drug receptor functions as a bacterial “oxygen” sensor. Proc Natl Acad Sci 94:5101–5106

    Article  ADS  Google Scholar 

  • Yin L, Wu N, Curtin JC, Qatanani M, Szwergold NR, Reid RA, Waitt GM, Parks DJ, Pearce KH, Wisely GB et al (2007) Rev-erbα, a heme sensor that coordinates metabolic and circadian pathways. Science 318:1786–1789

    Article  ADS  Google Scholar 

  • Zeno S, Zaaroor M, Leschiner S, Veenman L, Gavish M (2009) CoCl(2) induces apoptosis via the 18 kDa translocator protein in U118MG human glioblastoma cells. Biochemistry (Mosc) 48:4652–4661

    Article  Google Scholar 

  • Zhao AH, Tu LN, Mukai C, Sirivelu MP, Pillai VV, Morohaku K, Cohen R, Selvaraj V (2015) Mitochondrial translocator protein (TSPO) function is not essential for heme biosynthesis. J Biol Chem 291:1591–1603

    Article  Google Scholar 

  • Zhou T, Dang Y, Zheng Y-H (2014) The mitochondrial translocator protein, TSPO, inhibits HIV-1 envelope glycoprotein biosynthesis via the endoplasmic reticulum-associated protein degradation pathway. J Virol 88:3474–3484

    Article  Google Scholar 

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Acknowledgements

The research activities on TSPO led by M.C. are supported by the following funders gratefully acknowledged: Biotechnology and Biological Sciences Research Council [grant number BB/M010384/1]; the Medical Research Council [grant number G1100809/2]; Bloomsbury Colleges Consortium PhD Studentship Scheme; the London Interdisciplinary Biosciences Consortium; the Petplan Charitable Trust; Umberto Veronesi Foundation, Marie Curie Actions, the LAM-Bighi Grant Initiative and the Italian Ministry of Health [IFO14/01/R/52].

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  1. Department of Comparative Biomedical Sciences, The Royal Veterinary College, University of London, Royal College Street, NW1 0TU, London, UK

    Michele Frison, Anna Katherina Mallach, Emma Kennedy & Michelangelo Campanella

  2. University College London Consortium for Mitochondrial Research, Gower Street, WC1E 6BT, London, UK

    Michelangelo Campanella

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Frison, M., Mallach, A.K., Kennedy, E., Campanella, M. (2017). The 18 kDa Translocator Protein (TSPO): Cholesterol Trafficking and the Biology of a Prognostic and Therapeutic Mitochondrial Target. In: Rostovtseva, T. (eds) Molecular Basis for Mitochondrial Signaling. Biological and Medical Physics, Biomedical Engineering. Springer, Cham. https://doi.org/10.1007/978-3-319-55539-3_11

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