Complex role of the mitochondrial targeting signal in the function of steroidogenic acute regulatory protein revealed by bacterial artificial chromosome transgenesis in vivo
Open accessAbstract
The steroidogenic acute regulatory protein (StAR) stimulates the regulated production of steroid hormones in the adrenal cortex and gonads by facilitating the delivery of cholesterol to the inner mitochondrial membrane. To explore key aspects of StAR function within bona fide steroidogenic cells, we used a transgenic mouse model to explore the function of StAR proteins in vivo. We first validated this transgenic bacterial artificial chromosome reconstitution system by targeting enhanced green fluorescent protein to steroidogenic cells of the adrenal cortex and gonads. Thereafter, we targeted expression of either wild-type StAR (WT-StAR) or a mutated StAR protein lacking the mitochondrial targeting signal (N47-StAR). In the context of mice homozygous for a StAR knockout allele (StAR-/-), all StAR activity derived from the StAR transgenes, allowing us to examine the function of the proteins that they encode. The WT-StAR transgene consistently restored viability and steroidogenic function to StAR-/- mice. Although the N47-StAR protein was reportedly active in transfected COS cells and mitochondrial reconstitution experiments, the N47-StAR transgene rescued viability in only 40% of StAR-/- mice. Analysis of lipid deposits in the primary steroidogenic tissues revealed a hierarchy of StAR function provided by N47-StAR: florid lipid deposits were seen in the adrenal cortex and ovarian theca region, with milder deposits in the Leydig cells. Our results confirm the ability of StAR lacking its mitochondrial targeting signal to perform some essential functions in vivo but also demonstrate important functional defects that differ from in vitro studies obtained in nonsteroidogenic cells.
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The StAR mitochondrial presequence has biological necessity, as mouse models in which full-length StAR was replaced by StAR lacking the mitochondrial targeting sequence stochastically exhibit the CAH phenotype of steroidogenic failure.
“Interestingly, however, in vivo work has demonstrated that the StAR mitochondrial presequence has biological necessity, as mouse models in which full-length StAR has been replaced by StAR that lacks the mitochondrial targeting sequence stochastically exhibit the CAH phenotype of steroidogenic failure (140).”
From Adrenal Mitochondria and Steroidogenesis: From Individual Proteins to Functional Protein Assemblies (2016) · cites this paper as [140]
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- Authors
- Sasaki, G., Ishii, T., Jeyasuria, P., Jo, Y., Bahat, A., Orly, J., Hasegawa, T., & Parker, K. L.
- Affiliations
- Keio University (JP)
- Departments of Internal Medicine (G.S., T.I., P.J., Y.J., K.L.P.), Dallas, Texas 75390
- Hebrew University of Jerusalem (IL)
- The University of Texas Southwestern Medical Center (US)
- Corresponding author
- Parker, Keith L.
- Venue
- Molecular Endocrinology
- Publisher
- The Endocrine Society
- Published
- 2008-04-01
- Volume
- 22
- Issue
- 4
- Pages
- 951-964
- ISSN
- 0888-8809 (ISSN-L)
- 1944-9917
- PMC
- PMC2276465
- OpenAlex
- W2045515019
- Cited by
- 53
- References
- 41
- Citations by year
- 2026: 1 · 2025: 2 · 2024: 2 · 2023: 2 · 2021: 2 · 2020: 2 · 2019: 4 · 2018: 2 · 2017: 4 · 2016: 6 · 2015: 2 · 2014: 4 · 2013: 8 · 2012: 6
- FWCI
- 1.45
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Molecular Endocrinology (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Funders
- National Institute of Diabetes and Digestive and Kidney Diseases (DK54028, R01DK054028)
- Topics
- Health Sciences › Medicine › Endocrinology, Diabetes and Metabolism › Adrenal Hormones and Disorders
- Health Sciences › Medicine › Surgery › Cholesterol and Lipid Metabolism
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Steroid Chemistry and Biochemistry
- Keywords
- steroidogenic acute regulatory protein, mitochondrial targeting signal, cholesterol transport, steroidogenesis, adrenal cortex, gonads, Leydig cells, theca cells, lipid deposits, transgenic mouse model, steroidogenic cells
- MeSH terms
- Steroidogenic Acute Regulatory Protein, Adrenal Glands, Adrenocorticotropic Hormone, Animals, Corticosterone, Female, Gonads, Male, Mice, Transgenic, Mitochondria, Models, Genetic, Ovary, Phosphoproteins, Testis, Blotting, Southern, Immunoblotting, Gene Transfer Techniques, Reverse Transcriptase Polymerase Chain Reaction, Protein Transport, Chromosomes, Artificial, Bacterial, Mice
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