TSPO Finds NOX2 in Microglia for Redox Homeostasis

Guilarte, Tomás R.; Loth, Meredith K.; Guariglia, Sara R.

doi:10.1016/j.tips.2016.02.008

Cited by 58 publications

(64 citation statements)

References 64 publications

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“…A number of other recent reviews 37–43 illustrate the strong interest in the much-debated physiological functions and drug target potential of this multifaceted protein.…”

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confidence: 99%

Translocator Protein 18 kDa (TSPO): An Old Protein with New Functions?

et al. 2016

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Translocator protein 18 kDa (TSPO) was previously known as the peripheral benzodiazepine receptor (PBR) in eukaryotes, where it is mainly localized to the mitochondrial outer membrane. Considerable evidence indicates that it plays regulatory roles in steroidogenesis and apoptosis and is involved in various human diseases, such as metastatic cancer, Alzheimer’s and Parkinson’s disease, inflammation, and anxiety disorders. Ligands of TSPO are widely used as diagnostic tools and treatment options, despite there being no clear understanding of the function of TSPO. An ortholog in the photosynthetic bacterium Rhodobacter was independently discovered as the tryptophan-rich sensory protein (TspO) and found to play a role in the response to changes in oxygen and light conditions that regulate photosynthesis and respiration. As part of this highly conserved protein family found in all three kingdoms, the rat TSPO is able to rescue the knockout phenotype in Rhodobacter, indicating functional as well as structural conservation. Recently, a major breakthrough in the field was achieved: the determination of atomic-resolution structures of TSPO from different species by several independent groups. This now allows us to reexamine the function of TSPO with a molecular perspective. In this review, we focus on recently determined structures of TSPO and their implications for potential functions of this ubiquitous multifaceted protein. We suggest that TSPO is an ancient bacterial receptor/stress sensor that has developed additional interactions, partners, and roles in its mitochondrial outer membrane environment in eukaryotes.

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“…A number of other recent reviews 37–43 illustrate the strong interest in the much-debated physiological functions and drug target potential of this multifaceted protein.…”

mentioning

confidence: 99%

Translocator Protein 18 kDa (TSPO): An Old Protein with New Functions?

et al. 2016

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“…Etifoxine (6‐chloro‐ N ‐ethyl‐4‐methyl‐4‐phenyl‐4H‐benzo[d][1,3]oxazin‐2‐amine), a TSPO/GABA A drug ligand with anxiolytic and anticonvulsant properties, is approved and marketed in France for the treatment of anxiety disorders, and studies are underway to treat peripheral nerve injuries and axonal neuropathies by regulating neurosteroid levels . Moreover, a series of studies have supported a role for TSPO in inflammatory processes in peripheral tissues and the nervous system as a response to injury and disease; this role could be either passive, with TSPO being the result of increased mitochondrial membrane biogenesis occurring during microglia proliferation, or active, possibly through the regulation of reactive oxygen species (ROS) and local steroid production . Interestingly, the process of steroid formation, mediated by cytochrome P450s monooxygenases, is one of the drivers of ROS production in steroidogenic cells …”

Section: Structure and Function Of Tspo In Steroid Hormone Biosynthesismentioning

confidence: 99%

Translocator protein (18 kDa): an update on its function in steroidogenesis

Papadopoulos

Fan

Zirkin

2018

J Neuroendocrinology

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about the role of this protein in steroid and heme synthesis. We review the data on the structure and function of TSPO, as well as the recent results obtained using various genetic animal models. Taken together, these studies suggest that TSPO is a unique mitochondrial pharmacological target for diseases that involve increased mitochondrial activity, including steroidogenesis. Although there is no known mammalian species that lacks TSPO, it is likely that, because of the importance of this ancient protein in evolution and mitochondrial function, redundant mechanisms may exist to replace it under circumstances when it is removed. K E Y W O R D Smitochondria, neuroactive steroids, steroids, translocator protein

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“…Third, a putative TSPO-NADPH oxidase 2 (NOX2) association has been proposed to play a role in ROS generation. In this model, TSPO is surmised to behave as a carrier or transporter for both cholesterol and heme (Guilarte et al 2016). Fourth, it has been proposed that TSPO attenuates ROS signaling by modulating tetrapyrrole metabolism (Batoko et al 2015).…”

Section: :1mentioning

confidence: 99%

“…The TSPO-VDAC relationship to ROS production has had contrasting results in similar TSPO overexpression studies (Gatliff et al 2014, Joo et al 2012. The TSPO-NOX2 association (Guilarte et al 2016), remains a hypothesis. The finding that cardiac-specific Tspo cΔ/Δ mice did not show any difference in the extent of ischemia reperfusion injury (Sileikyte et al 2014), a pathology that is partly directed by myocardial NOX2 (Braunersreuther et al 2013), seems to suggest that TSPO and NOX2 may not be a primary mechanism.…”

Section: :1mentioning

confidence: 99%

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Current status and future perspectives: TSPO in steroid neuroendocrinology

Selvaraj

2016

Journal of Endocrinology

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The mitochondrial translocator protein (TSPO), previously known as the peripheral benzodiazepine receptor (PBR), has received significant attention both as a diagnostic biomarker and as a therapeutic target for different neuronal disease pathologies. Recently, its functional basis believed to be mediating mitochondrial cholesterol import for steroid hormone production has been refuted by studies examining both in vivo and in vitro genetic Tspo-deficient models. As a result, there now exists a fundamental gap in the understanding of TSPO function in the nervous system, and its putative pharmacology in neurosteroid production. In this review, we discuss several recent findings in steroidogenic cells that are in direct contradiction to previous studies, and necessitate a re-examination of the purported role for TSPO in de novo neurosteroid biosynthesis. We critically examine the pharmacological effects of different TSPObinding drugs with particular focus on studies that measure neurosteroid levels. We highlight the basis of key misconceptions regarding TSPO that continue to pervade the literature, and the need for interpretation with caution to avoid negative impacts. We also summarize the emerging perspectives that point to new directions that need to be investigated for understanding the molecular function of TSPO, only after which the true potential of this therapeutic target in medicine may be realized.

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TSPO Finds NOX2 in Microglia for Redox Homeostasis

Cited by 58 publications

References 64 publications

Translocator Protein 18 kDa (TSPO): An Old Protein with New Functions?

Translocator Protein 18 kDa (TSPO): An Old Protein with New Functions?

Translocator protein (18 kDa): an update on its function in steroidogenesis

Current status and future perspectives: TSPO in steroid neuroendocrinology

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