The changing landscape in translocator protein (TSPO) function

Selvaraj, Vimal; Stocco, Douglas M.

doi:10.1016/j.tem.2015.02.007

Cited by 105 publications

(72 citation statements)

References 80 publications

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“…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).…”

Section: Mammalian Translocator Protein (Tspo)mentioning

confidence: 99%

“…Again, recent discovery of the molecular identity of MPTP (15) and direct testing of MPTP function in the absence of TSPO (16) disputed its direct involvement in cell death processes (reviewed in Ref. 4). These new developments have shifted focus of TSPO function to yet another molecule considered to be an endogenous ligand, protoporphyrin IX (PPIX) (17).…”

Section: Mammalian Translocator Protein (Tspo)mentioning

confidence: 99%

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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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Section: Mammalian Translocator Protein (Tspo)mentioning

confidence: 99%

Section: Mammalian Translocator Protein (Tspo)mentioning

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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“…TSPO has also been implicated in many other important physiological processes, including cellular respiration, immunomodulation and apoptosis. However, despite almost 40 years of study, the precise functional role of TSPO is still far from clear [5].…”

Section: Tspo As a Target For Pet Imagingmentioning

confidence: 99%

“…We introduce TSPO and highlight some of the challenges for PET imaging of this protein. For further details, the reader is directed to excellent reviews of TSPO biology [4,5], radioligand development [6][7][8], PET methodology [9][10][11][12] and applications [7,13].…”

Section: Introductionmentioning

confidence: 99%

Microglial positron emission tomography (PET) imaging in epilepsy: Applications, opportunities and pitfalls

Scott

Mahmud

Owen

et al. 2017

Seizure

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Neuroinflammation is increasingly implicated in epileptogenesis and epilepsy. Microglia are an important mediator of central nervous system inflammation, and the development of positron emission tomography (PET) radioligands which bind the Translocator Protein (TSPO), an outer mitochondrial membrane protein expressed by microglia, has enabled in vivo measurement of neuroinflammation. Here, we outline the principles and potential pitfalls of TSPO PET imaging in relation to epilepsy, and opportunities for using TSPO imaging as a biomarker for future antiinflammatory based therapeutics in epilepsy. in vivo measurement of neuroinflammation. Here, we outline the principles and potential pitfalls of TSPO PET imaging in relation to epilepsy, and opportunities for using TSPO imaging as a biomarker for future anti-inflammatory based therapeutics in epilepsy.

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“…TSPO is known to form a complex on the mitochondrial outer membrane with VDAC (porin in Drosophila) [21e23], but their function as a complex still remains disputable [24]. We therefore investigated whether TSPO-VDAC complex is involved in parkinmediated immune response.…”

Section: Mitochondrial Tspo-vdac Complex Is Involved In Parkinmediatementioning

confidence: 99%

Parkin-mediated responses against infection and wound involve TSPO-VDAC complex in Drosophila

Cho

Park

Chung

et al. 2015

Biochemical and Biophysical Research Communications

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The changing landscape in translocator protein (TSPO) function

Cited by 105 publications

References 80 publications

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

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

Microglial positron emission tomography (PET) imaging in epilepsy: Applications, opportunities and pitfalls

Parkin-mediated responses against infection and wound involve TSPO-VDAC complex in Drosophila

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