Rapid regulation of steroidogenesis by mitochondrial protein import

Most mitochondrial proteins are synthesized on cytoplasmic ribosomes and imported into mitochondria(1-3). 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(4-7), 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.