Abstract
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.
Highlights
Translocator protein (TSPO) has been considered a mitochondrial cholesterol transporter critical for steroid hormone production
The complete absence of TSPO protein expression in different tissues in TspoϪ/Ϫ mice was confirmed by both Western blots (Fig. 2B) and immunohistochemistry, using a monoclonal antibody that recognizes protein coded by exon 4
TSPO function is absolutely essential for steroid hormone biosynthesis [23], and global Tspo gene deletion results in early embryonic lethality in mice [41]
Summary
Translocator protein (TSPO) has been considered a mitochondrial cholesterol transporter critical for steroid hormone production. We questioned this model showing that PBR/TSPO expression is not required for in vivo testicular steroidogenesis [38] This result has raised a lot of questions and controversy regarding the current understanding of the precise PBR/TSPO-mediated functions in steroid hormone production [39]. In a review article published in 1997, it was claimed that efforts to generate a Pbr/Tspo gene-deleted model failed as a result of early embryonic mortality in PBR/TSPO-deficient mice [41] This led to the conclusion that in addition to steroidogenesis, TSPO is involved in basic functions that are critically necessary for embryonic development. With the primary objective of studying the role of PBR/TSPO in steroidogenesis and other vital functions (if any) that may be critical for embryonic development, we used a germ cell specific knock-out approach to generate Pbr/Tspo global gene-deleted mice. Our results are unexpected and contrary to the prevailing view in that we find PBR/TSPO knock-out mice are viable and fertile with no effects on steroid hormone biosynthesis
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