Translocator Protein in Mitochondrial Cholesterol Transport and the Pharmacology of Steroidogenesis

Abstract

Steroidogenesis begins with the transfer of cholesterol from intracellular stores into mitochondria through a complex formed of cytosolic proteins, such as the steroidogenesis acute regulatory protein and 14-3-3 adaptor, and outer mitochondrial membrane proteins Translocator Protein (TSPO) and Voltage Dependent Anion Channel (VDAC). TSPO is an evolutionary conserved 18-kDa high affinity drug- and cholesterol- binding protein expressed in high levels in steroid synthesizing cells. Aberrant expression of TSPO has been linked to cancer, neurodegeneration, neuropsychiatric disorders and primary hypogonadism. TSPO drug ligands have been proposed as therapeutic and monitoring agents for these diseases. In the brain, steroids are local regulators of neural development and excitability. Changes in neurosteroid levels are linked to neuropsychiatric and neurological disorders such as depression, anxiety and neurodegeneration. Local administration of neurosteroids is unfeasible, and treatment of patients with large amounts of neuroactive steroids unsafe. In the testis, reduced serum testosterone (T) is common among subfertile and infertile young men as well as aging men and is often associated with depression, metabolic syndrome, and reduced sexual function. Although T-replacement therapy has been the treatment of choice, there are numerous side-effects. Thus, there is a clear need for developing repair therapies that restore the brain's and testis’ abilities to make steroids. In vitro and in vivo studies, using animal models of disease, demonstrated that TSPO drug ligands increased neurosteroid production in neuropsychiatric disorders and T formation in hypogonadism. Moreover, peptides conjugated to 14-3-3e site of interaction with VDAC1 blocked 14-3-3e-VDAC1 and increased VDAC1-TSPO interactions in testis inducing T formation. In contrast, in constitutively steroid producing Leydig and adrenal cell tumors blocking TSPO function inhibits excessive steroid synthesis. TSPO and VDAC were identified as valid drug targets that control steroid formation both in vitro and in vivo.