Translocator protein (18 kDa): an update on its function in steroidogenesis

Abstract

Translocator protein (18 kDa), TSPO, is a ubiquitous mitochondrial protein. Studies of its responses to drug and endogenous ligands have shown TSPO to be involved either directly or indirectly in numerous biological functions, including mitochondrial cholesterol transport and steroid hormone biosynthesis, porphyrin transport and heme synthesis, apoptosis, cell proliferation, and anion transport. Localized to the outer mitochondrial membrane of steroidogenic cells, TSPO has been shown to associate with cytosolic and mitochondrial proteins as part of a large multiprotein complex involved in mitochondrial cholesterol transport, the rate-limiting step in steroidogenesis. There is general agreement as to the structure and pharmacology of TSPO. Stimulation of TSPO has been shown to have therapeutic use as anxiolytics by inducing allopregnanolone production in the brain, and also potentially for reestablishing androgen levels in hypogonadal aging animals. Until recently, there has been general agreement as to the role of TSPO in steroidogenesis. However, recent studies involving genetic depletion of TSPO in mice have created controversy about the role of this protein in steroid and heme synthesis. We review herein the data on TSPO's structure and function, and recent results using various genetic animal models. Taken together, these studies suggest that TSPO is a unique mitochondrial pharmacological target for diseases that involve increased mitochondrial activity, including steroidogenesis. Although there is no known mammalian species that lacks TSPO, it is likely that due to the importance of this ancient protein in evolution and mitochondrial function, redundant mechanisms may exist to replace it under circumstances when it is removed.

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