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Rapid regulation of steroidogenesis by mitochondrial protein import

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.

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Figure 1: Affixing StAR to the outer mitochondrial membrane increases activity.
Figure 2: StAR is inactive in the intramembraneous space.
Figure 3: Association of StAR activity with mitochondrial import.
Figure 4: Full-length and N-62 StAR are equally active.

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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.).

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Correspondence to Walter L. Miller.

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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

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