Abstract
Most mitochondrial proteins are synthesized on cytoplasmic ribosomes and imported into mitochondria1,2,3. The imported proteins are directed to one of four submitochondrial compartments—the outer mitochondrial membrane, the inner mitochondrial membrane, the intramembraneous space, or the matrix—where the protein then functions. Here we show that the steroidogenic acute regulatory protein (StAR), a mitochondrial protein required for stress responses, reproduction, and sexual differentiation of male fetuses4,5,6,7, exerts its activity transiently at the outer mitochondrial membrane rather than at its final resting place in the matrix. We also show that its residence time at this outer membrane and its activity are regulated by its speed of mitochondrial import. This may be the first example of a mitochondrial protein exerting its biological activity in a compartment other than that to which it is finally targeted. This system enables steroidogenic cells to initiate and terminate massive levels of steroidogenesis within a few minutes, permitting the rapid regulation of serum steroid hormone concentrations.
This is a preview of subscription content, access via your institution
Access options
Subscribe to this journal
Receive 51 print issues and online access
$199.00 per year
only $3.90 per issue
Buy this article
- Purchase on Springer Link
- Instant access to full article PDF
Prices may be subject to local taxes which are calculated during checkout
Similar content being viewed by others
References
Schatz, G. & Dobberstein, B. Common principles of protein translocation across membranes. Science 271, 1519–1526 (1996)
Neupert, W. Protein import into mitochondria. Annu. Rev. Biochem. 66, 863–917 (1997)
Bauer, M. F. & Neupert, W. Import of proteins into mitochondria: A novel pathomechanism for progressive neurodegeneration. J. Inher. Metab. Dis. 24, 166–180 (2001)
Clark, B. J., Wells, J., King, S. R. & Stocco, D. M. The purification, cloning and expression of a novel luteinizing hormone-induced mitochondrial protein in MA-10 mouse Leydig tumour cells. Characterization of the steroidogenic acute regulatory protein (StAR). J. Biol. Chem. 269, 28314–28322 (1994)
Lin, D. et al. Role of steroidogenic acute regulatory protein in adrenal and gonadal steroidogenesis. Science 267, 1828–1831 (1995)
Stocco, D. M. & Clark, B. J. Regulation of the acute production of steroids in steroidogenic cells. Endocr. Rev. 17, 221–244 (1996)
Bose, H. S., Sugawara, T., Strauss, J. F. III & Miller, W. L. The pathophysiology and genetics of congenital lipoid adrenal hyperplasia. N. Engl. J. Med. 335, 1870–1878 (1996)
Miller, W. L. Molecular biology of steroid hormone synthesis. Endocr. Rev. 9, 295–318 (1988)
Arakane, F. et al. Steroidogenic acute regulatory protein (StAR) retains activity in the absence of its mitochondrial targeting sequence: Implications for the mechanism of StAR action. Proc. Natl Acad. Sci. USA 93, 13731–13736 (1996)
Kallen, C. B. et al. Steroidogenic acute regulatory protein (StAR) is a sterol transfer protein. J. Biol. Chem. 273, 26285–26288 (1998)
Miller, W. L. & Strauss, J. F. III Molecular pathology and mechanism of action of the steroidogenic acute regulatory protein, StAR. J. Steroid Biochem. Mol. Biol. 69, 131–141 (1999)
Bose, H. S., Whittal, R. M., Baldwin, M. A. & Miller, W. L. The active form of the steroidogenic acute regulatory protein, StAR, appears to be a molten globule. Proc. Natl Acad. Sci. USA 96, 7250–7255 (1999)
Song, M., Shao, K., Mujeeb, A., James, T. L. & Miller, W. L. Molten globule structure and membrane binding of the N-terminal protease-resistant domain (63-193) of the steroidogenic acute regulatory protein (StAR). Biochem. J. 356, 151–158 (2001)
Christinsen, K., Bose, H. S., Harris, F. M., Miller, W. L. & Bell, J. D. Binding of StAR to synthetic membranes suggests an active molten globule. J. Biol. Chem. 276, 17044–17051 (2001)
Tsujishita, Y. & Hurley, J. H. Structure and lipid transport mechanism of a StAR-related domain. Nature Struct. Biol. 7, 408–414 (2000)
Harikrishna, J. A., Black, S. M., Szklarz, G. D. & Miller, W. L. Construction and function of fusion enzymes of the human cytochrome P450scc system. DNA Cell Biol. 12, 371–379 (1993)
Abe, Y. et al. Structural basis of presequence recognition by the mitochondrial import receptor Tom20. Cell 100, 551–560 (2000)
Jefcoate, C. R., Simpson, E. R. & Boyd, G. S. Spectral properties of rat adrenal-mitochondrial cytochrome P-450. Eur. J. Biochem. 42, 539–551 (1974)
Toaff, M. E., Schleyer, H. & Strauss, J. F. III Metabolism of 25-hydroxycholesterol by rat luteal mitochondria and dispersed cells. Endocrinology 111, 1785–1790 (1982)
Bose, H. S., Whittal, R. M., Huang, M. C., Baldwin, M. A. & Miller, W. L. N-218 MLN64, a protein with StAR-like steroidogenic activity is folded and cleaved similarly to StAR. Biochemistry 39, 11722–11731 (2000)
Rapoport, D. & Neupert, W. Biogenesis of Tom40, core component of the Tom complex of mitochondria. J. Cell. Biol. 146, 321–331 (1999)
Li, J. M. & Shore, G. C. Reversal of the orientation of an integral protein of the mitochondrial outer membrane. Science 256, 1815–1817 (1992)
Meisinger, C. et al. Protein import channel of the outer mitochondrial membrane a highly stable Tom 40-Tom 20 core structure differentially interacts with preproteins, small Tom proteins and import receptors. Mol. Cell Biol. 21, 2337–2348 (2001)
Regan, C. I. W. M., Darley-Usmar, V. M. & Lowe, P. N. in Mitochondria: A Practical Approach (eds Darly-Usmar, V. M., Rickwood, D. & Wilson, M. T.) 79–112 (IRL Press, Washington DC, 1987)
Artemenko, I. P., Zhao, D., Hales, D. B., Hales, K. H. & Jefcoate, C. R. Mitochondrial processing of newly synthesized steroidogenic acute regulatory protein (StAR), but not total StAR, mediates cholesterol transfer to cytochrome P450 side chain cleavage enzyme in adrenal cells. J. Biol. Chem. 276, 46583–46596 (2001)
Bose, H. S., Baldwin, M. A. & Miller, W. L. Incorrect folding of steroidogenic acute regulatory protein (StAR) in congenital lipoid adrenal hyperplasia. Biochemistry 37, 9768–9775 (1998)
Hurt, E. C., Pesold-Hurt, B., Suda, K., Oppliger, W. & Schatz, G. The first twelve amino acids (less than half of the pre-sequence) of an imported mitochondrial protein can direct mouse cytosolic dihydrofolate reductase into the yeast mitochondrial matrix. EMBO J. 4, 2061–2068 (1985)
Chung, B., Matteson, K. J., Voutilainen, R., Mohandas, T. K. & Miller, W. L. Human cholesterol side-chain cleavage enzyme, P450scc: cDNA cloning, assignment of the gene to chromosome 15, and expression in the placenta. Proc. Natl Acad. Sci. USA 83, 8962–8966 (1986)
Chuck, S. & Lingappa, V. Apolipoprotein B intermediates. Nature 356, 115–116 (1992)
Luciano, P. et al. Functional reconstitution of the import of the yeast ADP/ATP carrier mediated by the TIM 10 complex. EMBO J. 20, 4099–4016 (2001)
Acknowledgements
We thank G. C. Shore for the Tom20 antiserum. This work was supported by the National Institutes of Health (H.B., V.R.L. and W.L.M.), the American Heart Association and the Sandler Foundation (V.R.L.), and the UCSF Academic Senate (W.L.M.).
Author information
Authors and Affiliations
Corresponding author
Ethics declarations
Competing interests
The authors declare that they have no competing financial interests
Rights and permissions
About this article
Cite this article
Bose, H., Lingappa, V. & Miller, W. Rapid regulation of steroidogenesis by mitochondrial protein import. Nature 417, 87–91 (2002). https://doi.org/10.1038/417087a
Received:
Accepted:
Issue Date:
DOI: https://doi.org/10.1038/417087a
This article is cited by
-
Multifaceted mitochondria: moving mitochondrial science beyond function and dysfunction
Nature Metabolism (2023)
-
Genomic and physiological resilience in extreme environments are associated with a secure attachment style
Translational Psychiatry (2020)
-
Effects of Butylparaben Supplementation on In Vitro Development of Mouse Preantral Follicle
Reproductive Sciences (2020)
-
Socioeconomic Deprivation, Adverse Childhood Experiences and Medical Disorders in Adulthood: Mechanisms and Associations
Molecular Neurobiology (2019)
-
Chronic low-dose exposure to a mixture of environmental endocrine disruptors induces microRNAs/isomiRs deregulation in mouse concomitant with intratesticular estradiol reduction
Scientific Reports (2017)
Comments
By submitting a comment you agree to abide by our Terms and Community Guidelines. If you find something abusive or that does not comply with our terms or guidelines please flag it as inappropriate.