Translocator protein/peripheral benzodiazepine receptor is not required for steroid hormone biosynthesis

Kanako Morohaku, Susanne H. Pelton, Daniel J. Daugherty, W. Ronald Butler, Wenbin Deng, Vimal Selvaraj

Research output: Contribution to journalArticle

133 Citations (Scopus)

Abstract

Molecular events that regulate cellular biosynthesis of steroid hormones have been a topic of intense research for more than half a century. It has been established that transport of cholesterol into the mitochondria forms the rate-limiting step in steroid hormone production. In current models, both the steroidogenic acute regulatory protein (StAR)andthe translocator protein (TSPO) have been implicated to have a concerted and indispensable effort in this cholesterol transport. Deletion of StAR in mice resulted in a critical failure of steroid hormone production, but deletion of TSPO in mice was found to be embryonic lethal. As a result, the role of TSPO in cholesterol transport has been established only using pharmacologic and genetic tools in vitro. To allow us to explore in more detail the function of TSPO in cell type-specific experimental manipulations in vivo, we generated mice carrying TSPO floxed alleles (TSPOfl/fl). In this study we made conditional knockout mice (TSPOcδ/δ) with TSPO deletion in testicular Leydig cells by crossing with an anti-Mullerian hormone receptor type II cre/+ mouse line. Genetic ablation of TSPO in steroidogenic Leydig cells in mice did not affect testosterone production, gametogenesis, and reproduction. Expression of StAR, cytochrome P450 side chain cleavage enzyme, 3β-hydroxysteroid dehydrogenase/δ5-δ4 isomerase type I, and TSPO2 in TSPOcδ/δ testis was unaffected. These results challenge the prevailing dogma that claims an essential role for TSPO in steroid hormone biosynthesis and force reexamination of functional interpretations made for this protein. This is the first study examining conditional TSPO gene deletion in mice. The results show that TSPO function is not essential for steroid hormone biosynthesis.

Original languageEnglish (US)
Pages (from-to)89-97
Number of pages9
JournalEndocrinology
Volume155
Issue number1
DOIs
StatePublished - Jan 2014

Fingerprint

GABA-A Receptors
Steroids
Hormones
Proteins
Leydig Cells
Cholesterol
3-Hydroxysteroid Dehydrogenases
Gametogenesis
Isomerases
Gene Deletion
Knockout Mice
Cytochrome P-450 Enzyme System
Reproduction
Testosterone
Testis
Mitochondria
Alleles

ASJC Scopus subject areas

  • Endocrinology

Cite this

Translocator protein/peripheral benzodiazepine receptor is not required for steroid hormone biosynthesis. / Morohaku, Kanako; Pelton, Susanne H.; Daugherty, Daniel J.; Butler, W. Ronald; Deng, Wenbin; Selvaraj, Vimal.

In: Endocrinology, Vol. 155, No. 1, 01.2014, p. 89-97.

Research output: Contribution to journalArticle

Morohaku, Kanako ; Pelton, Susanne H. ; Daugherty, Daniel J. ; Butler, W. Ronald ; Deng, Wenbin ; Selvaraj, Vimal. / Translocator protein/peripheral benzodiazepine receptor is not required for steroid hormone biosynthesis. In: Endocrinology. 2014 ; Vol. 155, No. 1. pp. 89-97.
@article{d29d943895e54c1eb3e492a3ebc30a31,
title = "Translocator protein/peripheral benzodiazepine receptor is not required for steroid hormone biosynthesis",
abstract = "Molecular events that regulate cellular biosynthesis of steroid hormones have been a topic of intense research for more than half a century. It has been established that transport of cholesterol into the mitochondria forms the rate-limiting step in steroid hormone production. In current models, both the steroidogenic acute regulatory protein (StAR)andthe translocator protein (TSPO) have been implicated to have a concerted and indispensable effort in this cholesterol transport. Deletion of StAR in mice resulted in a critical failure of steroid hormone production, but deletion of TSPO in mice was found to be embryonic lethal. As a result, the role of TSPO in cholesterol transport has been established only using pharmacologic and genetic tools in vitro. To allow us to explore in more detail the function of TSPO in cell type-specific experimental manipulations in vivo, we generated mice carrying TSPO floxed alleles (TSPOfl/fl). In this study we made conditional knockout mice (TSPOcδ/δ) with TSPO deletion in testicular Leydig cells by crossing with an anti-Mullerian hormone receptor type II cre/+ mouse line. Genetic ablation of TSPO in steroidogenic Leydig cells in mice did not affect testosterone production, gametogenesis, and reproduction. Expression of StAR, cytochrome P450 side chain cleavage enzyme, 3β-hydroxysteroid dehydrogenase/δ5-δ4 isomerase type I, and TSPO2 in TSPOcδ/δ testis was unaffected. These results challenge the prevailing dogma that claims an essential role for TSPO in steroid hormone biosynthesis and force reexamination of functional interpretations made for this protein. This is the first study examining conditional TSPO gene deletion in mice. The results show that TSPO function is not essential for steroid hormone biosynthesis.",
author = "Kanako Morohaku and Pelton, {Susanne H.} and Daugherty, {Daniel J.} and Butler, {W. Ronald} and Wenbin Deng and Vimal Selvaraj",
year = "2014",
month = "1",
doi = "10.1210/en.2013-1556",
language = "English (US)",
volume = "155",
pages = "89--97",
journal = "Endocrinology",
issn = "0013-7227",
publisher = "The Endocrine Society",
number = "1",

}

TY - JOUR

T1 - Translocator protein/peripheral benzodiazepine receptor is not required for steroid hormone biosynthesis

AU - Morohaku, Kanako

AU - Pelton, Susanne H.

AU - Daugherty, Daniel J.

AU - Butler, W. Ronald

AU - Deng, Wenbin

AU - Selvaraj, Vimal

PY - 2014/1

Y1 - 2014/1

N2 - Molecular events that regulate cellular biosynthesis of steroid hormones have been a topic of intense research for more than half a century. It has been established that transport of cholesterol into the mitochondria forms the rate-limiting step in steroid hormone production. In current models, both the steroidogenic acute regulatory protein (StAR)andthe translocator protein (TSPO) have been implicated to have a concerted and indispensable effort in this cholesterol transport. Deletion of StAR in mice resulted in a critical failure of steroid hormone production, but deletion of TSPO in mice was found to be embryonic lethal. As a result, the role of TSPO in cholesterol transport has been established only using pharmacologic and genetic tools in vitro. To allow us to explore in more detail the function of TSPO in cell type-specific experimental manipulations in vivo, we generated mice carrying TSPO floxed alleles (TSPOfl/fl). In this study we made conditional knockout mice (TSPOcδ/δ) with TSPO deletion in testicular Leydig cells by crossing with an anti-Mullerian hormone receptor type II cre/+ mouse line. Genetic ablation of TSPO in steroidogenic Leydig cells in mice did not affect testosterone production, gametogenesis, and reproduction. Expression of StAR, cytochrome P450 side chain cleavage enzyme, 3β-hydroxysteroid dehydrogenase/δ5-δ4 isomerase type I, and TSPO2 in TSPOcδ/δ testis was unaffected. These results challenge the prevailing dogma that claims an essential role for TSPO in steroid hormone biosynthesis and force reexamination of functional interpretations made for this protein. This is the first study examining conditional TSPO gene deletion in mice. The results show that TSPO function is not essential for steroid hormone biosynthesis.

AB - Molecular events that regulate cellular biosynthesis of steroid hormones have been a topic of intense research for more than half a century. It has been established that transport of cholesterol into the mitochondria forms the rate-limiting step in steroid hormone production. In current models, both the steroidogenic acute regulatory protein (StAR)andthe translocator protein (TSPO) have been implicated to have a concerted and indispensable effort in this cholesterol transport. Deletion of StAR in mice resulted in a critical failure of steroid hormone production, but deletion of TSPO in mice was found to be embryonic lethal. As a result, the role of TSPO in cholesterol transport has been established only using pharmacologic and genetic tools in vitro. To allow us to explore in more detail the function of TSPO in cell type-specific experimental manipulations in vivo, we generated mice carrying TSPO floxed alleles (TSPOfl/fl). In this study we made conditional knockout mice (TSPOcδ/δ) with TSPO deletion in testicular Leydig cells by crossing with an anti-Mullerian hormone receptor type II cre/+ mouse line. Genetic ablation of TSPO in steroidogenic Leydig cells in mice did not affect testosterone production, gametogenesis, and reproduction. Expression of StAR, cytochrome P450 side chain cleavage enzyme, 3β-hydroxysteroid dehydrogenase/δ5-δ4 isomerase type I, and TSPO2 in TSPOcδ/δ testis was unaffected. These results challenge the prevailing dogma that claims an essential role for TSPO in steroid hormone biosynthesis and force reexamination of functional interpretations made for this protein. This is the first study examining conditional TSPO gene deletion in mice. The results show that TSPO function is not essential for steroid hormone biosynthesis.

UR - http://www.scopus.com/inward/record.url?scp=84891379545&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=84891379545&partnerID=8YFLogxK

U2 - 10.1210/en.2013-1556

DO - 10.1210/en.2013-1556

M3 - Article

AN - SCOPUS:84891379545

VL - 155

SP - 89

EP - 97

JO - Endocrinology

JF - Endocrinology

SN - 0013-7227

IS - 1

ER -