118 Chapter 5 from structural cholesterol and facilitating its import into the mitochondria for steroid and formation is obvious, for other cells it is not so clear. However, cholesterol transfer in the inner mitochondrial membrane is needed for biogenesis of mitochondrial membranes during cell proliferation and/or repair. TSPO may also function as a sink for cholesterol which when free could be toxic for the cells. It is also possible that TSPO may be facilitating the movement of free cholesterol from the mitochondria to other organelles, as shown in astrocytes71, fibroblasts71, macrophages97, retinal cells98 and the steroidogenic Leydig cells72. Moreover, TSPO-mediated accumulation of free cholesterol in the mitochondria may affect mitochondrial membrane fluidity/permeability, fission/fusion processes, membrane protein/ transporter function(s), and/or membrane potential71,82,99-101. TSPO was also shown to regulate mitophagy58,102. TSPO, by binding to VDAC1, reduces mitochondrial coupling and promotes an overproduction of ROS that counteracts parkinmediated ubiquitination of proteins. These data suggested TSPO as an element in the regulation of mitochondrial quality control by autophagy. Further studies showed that TSPO deregulates mitochondrial Ca2+ signalling, leading to a parallel increase in the cytosolic Ca2+ pools that activate the Ca2+-dependent NADPH oxidase, thereby increasing ROS103. The inhibition of mitochondrial Ca2+ uptake by TSPO is a consequence of the phosphorylation of VDAC1 by PKA, which is recruited to the mitochondria by ACBD3, VDAC1, ACBD3, PKA, and all transduceosome components recruited at TSPO. This is proposed as a novel OMM-based pathway to control intracellular Ca2+ dynamics and redox transients in cytotoxicity103. Genetics and genetic models A series of articles came out in the last 15 years assessing the direct role of TSPO in various cellular pathways. First, the role of TSPO in opening the MPTP in liver mitochondrial function was investigated in an animal model depleted of liver TSPO104. The data obtained showed that the absence of TSPO does not affect liver MPTP function. Then, studies in rodents with genetic depletion of TSPO led to conflicting results including no effect on steroid synthesis105-107, reduced steroid output, inhibition of corticosteroid response to adrenocorticotropic hormone, changes in lipid homeostasis in Leydig cells and reduction of circulating testosterone levels, and suppression of neurosteroid formation108-111. In addition, discordant data was reported on MA-10 mouse Leydig cells. Knockdown of TSPO expression using antisense oligonucleotides or antisense RNA reduces the ability of the cells to form steroids, while CRISPR/Cas9-guided TSPO deletion has either no effect or abolishes steroid synthesis112-115. These differences have been discussed in detail in other reviews65,66. Among all these studies, it seems that there is consistency between laboratories on the role of TSPO in neurosteroid formation where genetic deletion of TSPO led to reduced neurosteroid synthesis109,111. These results suggest that the role of TSPO in steroid formation may be primary and rate-determining in cells where steroid formation is independent on hormonal control, e.g. brain, compared to the classical peripheral steroid forming gonads and adrenal where pituitary hormones control the massive steroid production. In peripheral steroidogenic organs, TSPO may play a secondary role or play a role in cases where the cells do not respond to pituitary hormones, as in male hypogonadism where TSPO ligands can recover the drug- or age-induced reduction in androgen formation65. Numerous biochemical, pharmacological, and clinical data in the field of photodynamic therapy in oncology have demonstrated the role of ability of TSPO to bind porphyrins and its
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