Genetic analysis of <scp>dTSPO</scp>, an outer mitochondrial membrane protein, reveals its functions in apoptosis, longevity, and Aβ42‐induced neurodegeneration

Lin, Ran; Angelin, Alessia; Settimo, Federico Da; Martini, Claudia; Taliani, Sabrina; Zhu, Shi-En; Wallace, Douglas C.

doi:10.1111/acel.12200

Cited by 64 publications

(70 citation statements)

References 41 publications

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“…Tspo-knockout studies in another in vivo model, Drosophila melanogaster, indicated that Tspo −/− flies are without any abnormalities (Lin et al 2014), similar to reports in mice , Tu et al 2014. Interestingly, structures and cells in Tspo −/− flies showed increased survival after hydrogen peroxide exposure or γ-irradiation (Lin et al 2014).…”

Section: Tspo As a Regulator Of Oxygen Consumptionsupporting

confidence: 64%

“…Interestingly, structures and cells in Tspo −/− flies showed increased survival after hydrogen peroxide exposure or γ-irradiation (Lin et al 2014). In only male Tspo −/− flies, an extended lifespan was observed compared with male wild-type flies (Lin et al 2014). Isolated Tspo-deficient mitochondria from these flies, irrespective of sex, showed a decreased rate of oxidative phosphorylation compared with Tspo +/+ mitochondria (Lin et al 2014).…”

Section: Tspo As a Regulator Of Oxygen Consumptionmentioning

confidence: 95%

Section: Tspo As a Regulator Of Oxygen Consumptionmentioning

confidence: 96%

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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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Section: Tspo As a Regulator Of Oxygen Consumptionsupporting

confidence: 64%

Section: Tspo As a Regulator Of Oxygen Consumptionmentioning

confidence: 95%

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Current status and future perspectives: TSPO in steroid neuroendocrinology

Selvaraj

2016

Journal of Endocrinology

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“…Translocator protein expression is increased in elderly people and in patients with Alzheimer's disease (Kumar et al., 2012; Yasuno et al., 2008). Interestingly, inhibition of TSPO in drosophila inhibited apoptosis, extended fly lifespan, and inhibited Aβ peptide‐induced neurodegeneration (Lin et al., 2014). In addition, Elkamhawy et al.…”

Section: Evidence For the Involvement Of Mptp Opening In Age‐associatmentioning

confidence: 99%

Mitochondria and aging: A role for the mitochondrial transition pore?

2018

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SummaryThe cellular mechanisms responsible for aging are poorly understood. Aging is considered as a degenerative process induced by the accumulation of cellular lesions leading progressively to organ dysfunction and death. The free radical theory of aging has long been considered the most relevant to explain the mechanisms of aging. As the mitochondrion is an important source of reactive oxygen species (ROS), this organelle is regarded as a key intracellular player in this process and a large amount of data supports the role of mitochondrial ROS production during aging. Thus, mitochondrial ROS, oxidative damage, aging, and aging‐dependent diseases are strongly connected. However, other features of mitochondrial physiology and dysfunction have been recently implicated in the development of the aging process. Here, we examine the potential role of the mitochondrial permeability transition pore (mPTP) in normal aging and in aging‐associated diseases.

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“…It has been shown that PBR distributes ubiquitously in most types of tissues, including bone marrow stromal cells 14. Putative PBR functions are involved in numerous types of physiological processes, such as steroidogenesis, apoptosis, cell proliferation, regulation of mitochondrial membrane potential, mitochondria respiratory chains, voltage‐dependent calcium channels and microglial activation 11, 12, 15, 16, 17. PK11195 is a competitive antagonist that specifically binds to PBR18 and has been shown to reverse the inhibitory effect of Midazolam on the anxiolytic and antidepressant effects of Midazolam 19…”

Section: Introductionmentioning

confidence: 99%

Midazolam inhibits chondrogenesis via peripheral benzodiazepine receptor in human mesenchymal stem cells

Chen

Huang

et al. 2018

J Cellular Molecular Medi

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Midazolam, a benzodiazepine derivative, is widely used for sedation and surgery. However, previous studies have demonstrated that Midazolam is associated with increased risks of congenital malformations, such as dwarfism, when used during early pregnancy. Recent studies have also demonstrated that Midazolam suppresses osteogenesis of mesenchymal stem cells (MSCs). Given that hypertrophic chondrocytes can differentiate into osteoblast and osteocytes and contribute to endochondral bone formation, the effect of Midazolam on chondrogenesis remains unclear. In this study, we applied a human MSC line, the KP cell, to serve as an in vitro model to study the effect of Midazolam on chondrogenesis. We first successfully established an in vitro chondrogenic model in a micromass culture or a 2D high‐density culture performed with TGF‐β‐driven chondrogenic induction medium. Treatment of the Midazolam dose‐dependently inhibited chondrogenesis, examined using Alcian blue‐stained glycosaminoglycans and the expression of chondrogenic markers, such as SOX9 and type II collagen. Inhibition of Midazolam by peripheral benzodiazepine receptor (PBR) antagonist PK11195 or small interfering RNA rescued the inhibitory effects of Midazolam on chondrogenesis. In addition, Midazolam suppressed transforming growth factor‐β‐induced Smad3 phosphorylation, and this inhibitory effect could be rescued using PBR antagonist PK11195. This study provides a possible explanation for Midazolam‐induced congenital malformations of the musculoskeletal system through PBR.

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Genetic analysis of dTSPO, an outer mitochondrial membrane protein, reveals its functions in apoptosis, longevity, and Aβ42‐induced neurodegeneration

Cited by 64 publications

References 41 publications

Current status and future perspectives: TSPO in steroid neuroendocrinology

Current status and future perspectives: TSPO in steroid neuroendocrinology

Mitochondria and aging: A role for the mitochondrial transition pore?

Midazolam inhibits chondrogenesis via peripheral benzodiazepine receptor in human mesenchymal stem cells

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