2. Department of Pediatrics, University of California, San Francisco, California 94143-0978, USA
3. Department of Physiology, University of California, San Francisco, California 94143-0978, USA
4. Department of Medicine, University of California, San Francisco, California 94143-0978, USA
5. The Metabolic Research Unit, University of California, San Francisco, California 94143-0978, USA

Correspondence to: Walter L. Miller^1,4 Correspondence and request for materials should be addressed to W.L.M. (e-mail: Email: wlmlab@itsa.ucsf.edu).

Abstract

Most mitochondrial proteins are synthesized on cytoplasmic ribosomes and imported into mitochondria^{1, 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 fetuses^{4, 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.