The Comprehensive Steroidome in Complete TSPO/PBR Knockout Mice under Basal Conditions

• Published in: International journal of molecular sciences Vol. 24; no. 3; p. 2474
• Main Authors: Liere, Philippe, Liu, Guo-Jun, Pianos, Antoine, Middleton, Ryan J, Banati, Richard B, Akwa, Yvette
• Format: Journal Article
• Language: English
• Published: Switzerland MDPI AG 27.01.2023; MDPI
• Subjects: Adrenal glands; Androgens; Animals; Brain; Carrier Proteins; Cholesterol; Corticosterone; Dehydrogenases; Enzymes; Estrogens; Gas chromatography; Gene deletion; Genotypes; Glucocorticoids; Hormones; Life Sciences; Male; Males; Mass spectrometry; Mass spectroscopy; Membrane proteins; Metabolites; Mice; Mice, Inbred C57BL; Mice, Knockout; Mitochondria; neurosteroids; PBR; peripheral benzodiazepine receptor; Plasma; Pregnenolone; Progesterone; Proteins; Receptors, GABA - genetics; Receptors, GABA - metabolism; Reductases; Steroid 5α-reductase; Steroid hormones; Steroidogenesis; Steroids; Tandem Mass Spectrometry; Testes; Testosterone; translocator protein; TSPO; TspO gene; PBR; gene knockout; translocator protein; neurosteroids; mitochondria; steroidogenesis; TSPO; gas chromatography–tandem mass spectrometry; peripheral benzodiazepine receptor; endocrine glands; DIV: days in vitro; gLTP: glycine-induced long-term potentiation; autophagy; TFEB: transcription factor EB Alzheimer; neuron; tau; synapse; DBS: deep brain stimulation; deep brain stimulation; triple transgenic AD mice AD: Alzheimer disease CSA: cyclosporine A DBS: deep brain stimulation DIV: days in vitro EC: entorhinal cortex FTD: frontotemporal dementia gLTP: glycine-induced long-term potentiation GPi: internal segment of the globus pallidus PD: Parkinson disease STN: subthalamic nucleus TFEB: transcription factor EB Alzheimer autophagy deep brain stimulation lysosome neuron synapse tau; GPi: internal segment of the globus pallidus; PD: Parkinson disease; STN: subthalamic nucleus; triple transgenic AD mice; AD: Alzheimer disease; FTD: frontotemporal dementia; CSA: cyclosporine A; EC: entorhinal cortex; lysosome
• DOI: 10.3390/ijms24032474
• ISSN: 1422-0067; 1661-6596

The 18 kDa translocator protein (TSPO/PBR) is a multifunctional evolutionary highly conserved outer mitochondrial membrane protein. Decades of research has reported an obligatory role of TSPO/PBR in both mitochondrial cholesterol transport and, thus, steroid production. However, the strict dependency of steroidogenesis on TSPO/PBR has remained controversial. The aim of this study was to provide insight into the steroid profile in complete C57BL/6- -knockout male mice (TSPO-KO) under basal conditions. The steroidome in the brain, adrenal glands, testes and plasma was measured by gas chromatography coupled to tandem mass spectrometry (GC-MS/MS). We found that steroids present in wild-type (WT) mice were also detected in TSPO-KO mice, including pregnenolone (PREG), progestogens, mineralo-glucocorticosteroids and androgens. The concentrations of PREG and most metabolites were similar between genotypes, except a significant decrease in the levels of the 5α-reduced metabolites of progesterone (PROG) in adrenal glands and plasma and of the 5α-reduced metabolites of corticosterone (B) in plasma in TSPO-KO compared to WT animals, suggesting other regulatory functions for the TSPO/PBR. The expression levels of the voltage-dependent anion-selective channel (VDAC-1), CYP11A1 and 5α-reductase were not significantly different between both groups. Thus, the complete deletion of the tspo gene in male mice does not impair de novo steroidogenesis in vivo.