Peripheral Benzodiazepine Receptor/Translocator Protein Global Knock-out Mice Are Viable with No Effects on Steroid Hormone Biosynthesis

• Published in: The Journal of biological chemistry Vol. 289; no. 40; pp. 27444 - 27454
• Main Authors: Tu, Lan N., Morohaku, Kanako, Manna, Pulak R., Pelton, Susanne H., Butler, W. Ronald, Stocco, Douglas M., Selvaraj, Vimal
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 03.10.2014; American Society for Biochemistry and Molecular Biology
• Subjects: Animals; Developmental Biology; Female; Gonadal Steroid Hormones - biosynthesis; Leydig Cells - metabolism; Male; Mice; Mice, Inbred C57BL; Mice, Knockout; Receptors, GABA - genetics; Receptors, GABA - metabolism; Mitochondria; STAR; Gene Knock-out; TSPO; Steroidogenesis; Adrenal; Cholesterol
• ISSN: 0021-9258; 1083-351X
• DOI: 10.1074/jbc.M114.578286

Translocator protein (TSPO), previously known as the peripheral benzodiazepine receptor, is a mitochondrial outer membrane protein implicated as essential for cholesterol import to the inner mitochondrial membrane, the rate-limiting step in steroid hormone biosynthesis. Previous research on TSPO was based entirely on in vitro experiments, and its critical role was reinforced by an early report that claimed TSPO knock-out mice were embryonic lethal. In a previous publication, we examined Leydig cell-specific TSPO conditional knock-out mice that suggested TSPO was not required for testosterone production in vivo. This raised controversy and several questions regarding TSPO function. To examine the definitive role of TSPO in steroidogenesis and embryo development, we generated global TSPO null (Tspo−/−) mice. Contrary to the early report, Tspo−/− mice survived with no apparent phenotypic abnormalities and were fertile. Examination of adrenal and gonadal steroidogenesis showed no defects in Tspo−/− mice. Adrenal transcriptome comparison of gene expression profiles showed that genes involved in steroid hormone biosynthesis (Star, Cyp11a1, and Hsd3b1) were unchanged in Tspo−/− mice. Adrenocortical ultrastructure illustrated no morphological alterations in Tspo−/− mice. In an attempt to correlate our in vivo findings to previously used in vitro models, we also determined that siRNA knockdown or the absence of TSPO in different mouse and human steroidogenic cell lines had no effect on steroidogenesis. These findings directly refute the dogma that TSPO is indispensable for steroid hormone biosynthesis and viability. By amending the current model, this study advances our understanding of steroidogenesis with broad implications in biology and medicine.