Translocator protein-mediated pharmacology of cholesterol transport and steroidogenesis

Serum testosterone (TS) levels decrease with aging in both humans and rodents. Using the rat as a model system, it was found that age-related reductions in serum TS were not due to loss of Leydig cells, but rather to the reduced ability of the Leydig cells to produce TS in response to luteinizing hormone (LH). Detailed analyses of the steroidogenic pathway have suggested that two defects along the pathway, LH-stimulated cAMP production and cholesterol transport to and into the mitochondria, are of particular importance in age-related reductions in TS production. Although the mechanisms involved in these defects are far from certain, increasing oxidative stress appears to play a particularly important role. Interestingly, increased oxidative stress also appears to be involved in the suppressive effects of endocrine disruptors on Leydig cell TS production.Reproduction (2017) 154 R111-R122

show abstract

“…The latter results are disputed, however (Fan et al . 2015; Papadopoulos et al . 2015), and yet to be confirmed.…”

Section: Effects Of Aging On Steroidogenesismentioning

confidence: 99%

Steroidogenesis in Leydig cells: effects of aging and environmental factors

Wang¹,

Chen²,

Ye³

et al. 2017

Reproduction

Self Cite

196

110

View full text Add to dashboard Cite

show abstract

“…However, the viability of mice has been shown to vary depending on methodology: Nr5a1-driven conditional knock-outs were born at a normal Mendelian ratio while Amhr2-Cre driven conditional knock-outs were born at a ratio of 4.4% (111). Global Tspo knockout phenotypes can range from lethal, when whole gene deletion is performed, to no phenotype, as in the case of cre-loxP technique, thus presenting the possibility that methodological differences may be the cause of such discrepancy (112). Phenotypic characterization carried out on currently available global and conditional knock-out strains is summarized in Table 1.…”

Section: Tspo -/-Knockout Mice: New Insights Of An Old Functionmentioning

confidence: 99%

TSPO: kaleidoscopic 18-kDa amid biochemical pharmacology, control and targeting of mitochondria

Gatliff

Campanella

2016

Biochemical Journal

View full text Add to dashboard Cite

The 18-kDa translocator protein (TSPO) localizes in the outer mitochondrial membrane (OMM) of cells and is readily up-regulated under various pathological conditions such as cancer, inflammation, mechanical lesions and neurological diseases. Able to bind with high affinity synthetic and endogenous ligands, its core biochemical function resides in the translocation of cholesterol into the mitochondria influencing the subsequent steps of (neuro-)steroid synthesis and systemic endocrine regulation. Over the years, however, TSPO has also been linked to core cellular processes such as apoptosis and autophagy. It interacts and forms complexes with other mitochondrial proteins such as the voltage-dependent anion channel (VDAC) via which signalling and regulatory transduction of these core cellular events may be influenced. Despite nearly 40 years of study, the precise functional role of TSPO beyond cholesterol trafficking remains elusive even though the recent breakthroughs on its high-resolution crystal structure and contribution to quality-control signalling of mitochondria. All this along with a captivating pharmacological profile provides novel opportunities to investigate and understand the significance of this highly conserved protein as well as contribute the development of specific therapeutics as presented and discussed in the present review.

show abstract

“…The cholesterol-binding site has been localized to the C-terminal end of the fifth transmembrane helix of the protein at a phylogenetically The names and structures of proteins interacting with TSPO and modifying its ligand binding properties to compounds such as Ro5-4864 (shown between TSPO and VDAC). Cartoon structures of compounds drawn from PDB files using PyMOL [75]; conserved cholesterol recognition amino acid consensus (CRAC) motif [53]. Mutation of this motif eliminates specific cholesterol binding [54] and cholesterol uptake in transfected Escherichia coli [53].…”

Section: Tspo Crac Motif and Cholesterol Bindingmentioning

confidence: 99%

Translocator protein: pharmacology and steroidogenesis

Midzak

Zirkin

Papadopoulos

2015

Biochemical Society Transactions

Self Cite

View full text Add to dashboard Cite

The translocator protein (TSPO; 18k Da) is an evolutionarily conserved outer mitochondrial membrane (OMM) protein highly expressed in steroid-synthesizing cells and found to possess a number of physiological and drug-binding partners. Extensive pharmacological, biochemical and cell biological research over the years has led to a model of TSPO involvement in mitochondrial cholesterol transport and promotion of steroid synthesis, a model guiding the design of drugs useful in stimulating neurosteroid synthesis and alleviating psychopathological symptoms. The involvement of TSPO in these processes has been called into question; however, with the publication of TSPO-deletion mouse models which saw no changes in steroid production. Here, we review work characterizing TSPO in steroidogenesis and offer perspective to research into TSPO pharmacology and its involvement in steroid biosynthesis.

show abstract

Translocator protein-mediated pharmacology of cholesterol transport and steroidogenesis

Cited by 113 publications

References 121 publications

Steroidogenesis in Leydig cells: effects of aging and environmental factors

Steroidogenesis in Leydig cells: effects of aging and environmental factors

TSPO: kaleidoscopic 18-kDa amid biochemical pharmacology, control and targeting of mitochondria

Translocator protein: pharmacology and steroidogenesis

Contact Info

Product

Resources

About