Effects of peripheral benzodiazepines upon the O2 consumption of neuroblastoma cells

Larcher, Jean-Christopher; Vayssière, Jean-Luc; Marquer, Florence J. Le; Cordeau, Laurence; Keane, P.E.; Bachy, A; Gross, François; Croizat, Bernard

doi:10.1016/0014-2999(89)90843-1

Cited by 58 publications

(27 citation statements)

References 16 publications

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“…10 A role for TSPO in the execution of apoptosis has long been proposed and its natural and synthetic ligands i) endozepine, 11,12 ii) PK11195 [13][14][15][16] and iii) Ro-54864 17 are widely exploited as chemotherapy co-adjuvants. Other functions linked to TSPO include: i) the regulation of mitochondrial ATP production, 18,19 ii) the generation of reactive oxygen species, 20,21 and iii) the modulation of Ca 2C signaling. 22,23 Notably, its precise role in cell physiology has received relatively little attention, leaving its contribution to mitochondrial function largely illdefined.…”

Section: Introductionmentioning

confidence: 99%

TSPO interacts with VDAC1 and triggers a ROS-mediated inhibition of mitochondrial quality control

et al. 2014

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The 18-kDa TSPO (translocator protein) localizes on the outer mitochondrial membrane (OMM) and participates in cholesterol transport. Here, we report that TSPO inhibits mitochondrial autophagy downstream of the PINK1-PARK2 pathway, preventing essential ubiquitination of proteins. TSPO abolishes mitochondrial relocation of SQSTM1/p62 (sequestosome 1), and consequently that of the autophagic marker LC3 (microtubule-associated protein 1 light chain 3), thus leading to an accumulation of dysfunctional mitochondria, altering the appearance of the network. Independent of cholesterol regulation, the modulation of mitophagy by TSPO is instead dependent on VDAC1 (voltagedependent anion channel 1), to which TSPO binds, reducing mitochondrial coupling and promoting an overproduction of reactive oxygen species (ROS) that counteracts PARK2-mediated ubiquitination of proteins. These data identify TSPO as a novel element in the regulation of mitochondrial quality control by autophagy, and demonstrate the importance for cell homeostasis of its expression ratio with VDAC1.

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Section: Introductionmentioning

confidence: 99%

TSPO interacts with VDAC1 and triggers a ROS-mediated inhibition of mitochondrial quality control

et al. 2014

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“…3 and 4), may be due to off target effects. Early studies that utilized TSPO-binding drugs, PK11195 and Ro5-4864 (4Ј-chlorodiazepam) demonstrated that they could induce a dose-dependent decrease in OCR (62) and inhibit mitochondrial respiratory control (63), similar to that observed in Tspo Ϫ/Ϫ cells. However, given our results using PK11195 in Tspo Ϫ/Ϫ cells, it is clear that specificity of TSPO binding and off target effects may preclude the ability to interpret results from pharmacological studies.…”

Section: Discussionmentioning

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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“…A broad spectrum of putative functions has been suggested for the PBR (8), such as regulation of steroid production (4, 8 -12), involvement in cell growth and differentiation (12)(13)(14)(15), regulation of the mitochondrial respiratory chain (8,16,17), regulation of heme biosynthesis (8,18,19), effect on the immune and phagocytic host defense response (8,20), and modulation of voltage-dependent calcium channels (8). The first two of these functions are the most commonly suggested.…”

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confidence: 99%

Effects of Peripheral-type Benzodiazepine Receptor Antisense Knockout on MA-10 Leydig Cell Proliferation and Steroidogenesis

Kelly-Hershkovitz¹,

Weizman²,

Spanier³

et al. 1998

Journal of Biological Chemistry

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The peripheral-type benzodiazepine receptor (PBR) is not only widely expressed throughout the body, but it is also genetically conserved from bacteria to humans. Many functions have been attributed to it, but its primary role remains a puzzle. In the current study, we stably transfected cultures of MA-10 Leydig cells with either control or 18-kDa PBR antisense knockout plasmids. The antisense knockout vector was driven by the human enkephalin promoter, which contains two cAMP response elements, such that cAMP treatment of transfected cells could superinduce 18-kDa PBR antisense RNA transcription and, hence, down-regulate endogenous 18-kDa PBR mRNA levels. Control and knockout MA-10 cell lines were then compared at the level of receptor binding, thymidine incorporation, and steroid biosynthesis. Eighteen-kilodalton PBR knockout reduced the maximal binding capacity of tritium-labeled PBR ligands, and the affinity of receptors to the ligands remained unaltered. Additionally, 24-h accumulation of progesterone was lower in the knockout cells. Exposure of the two cell types to 8-bromo-cAMP resulted in a robust increase in steroid production. However, a complex pattern of steroid accumulation was observed, in which further progestin metabolism was indicated. The later decline in accumulated progesterone as well as the synthesis of androstenedione were different in the two cell types. At the level of cell proliferation, reduction of 18-kDa PBR mRNA showed no effect. Thus, we conclude that the 18-kDa PBR may have a more important role in steroidogenesis than in proliferation in this Leydig cell line.

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Effects of peripheral benzodiazepines upon the O2 consumption of neuroblastoma cells

Cited by 58 publications

References 16 publications

TSPO interacts with VDAC1 and triggers a ROS-mediated inhibition of mitochondrial quality control

TSPO interacts with VDAC1 and triggers a ROS-mediated inhibition of mitochondrial quality control

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

Effects of Peripheral-type Benzodiazepine Receptor Antisense Knockout on MA-10 Leydig Cell Proliferation and Steroidogenesis

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