119 TSPO expression in healthy and diseased brain role in porphyrin and heme transport and synthesis116-118. Using the same mice as before106 the same group failed to show a role for TSPO in porphyrin and heme biosynthesis or transport119. TSPO deficiency decreased the oxygen consumption rate and mitochondrial membrane potential in mouse fibroblasts119, MA-10 mouse Leydig cells115 and C20 human microglia cells where it also reduced respiratory function120. Mitochondrial membrane potential depends on the flux of respiratory substrates adenosine triphosphate, adenosine diphosphate, and Pi through VDAC. Adenine nucleotide translocator also plays a role in maintenance of the membrane potential115. Therefore, TSPO likely controls cellular andmitochondrial metabolism via regulation of the mitochondrial membrane potential and affects OMM permeability and/ or outer and inner membrane contacts/fusion. Interestingly, lack of TSPO was shown to affect mitochondrial respiration and increase oxygen consumption in some cell and animal Tspo KO models, but not in others62,64,78,106,107,119,120. More recent studies also failed to show a direct link of TSPO to F-ATP synthase, which was shown to form the MPTP121. The differences underlying the disparate results from these genetic animal and cell models are not well understood. However, they clearly indicate differences between the pharmacology of TSPO and its intrinsic cellular functions. It is also likely that species differences, the presence of external or intrinsic stimuli, as well as differences in age, sex, and metabolic status of the species used may control the expression of TSPO. Considering that TSPO is one of the evolutionarily oldest proteins (see below), we proposed that it serves as the basis for fundamental functions and, thus, in case of its absence, compensatory mechanisms may have evolved. Moreover, even if its absence may not always affect animal phenotype, its presence, concentrated at the OMM, plays a regulatory role in mitochondrial function and associated tissue-specific phenotypes. Moreover, its presence provides us with a molecular target able to modulate mitochondrial and cell functions. TSPO genetics in humans provide some of the most important information on the function of this protein. No humans have been identified lacking TSPO. In humans, the presence of a number of polymorphisms have been identified in the TSPO gene, including rs6971122. This polymorphism causes a non-conservative amino acid substitution, Ala147Thr, resulting in altered binding affinity of TSPO for specific ligands122. The presence of this TSPO polymorphism has been linked to the function of the hypothalamic-pituitary-adrenal axis, predisposing carriers to psychiatric disorders123-126, and potentially impairing the response of patients to anxiolytic TSPO drug ligands127,128. The presence of this TSPO polymorphism was linked to reduced pregnenolone129 and adrenocorticotropic hormone (ACTH)-induced corticosteroid levels109 and shown to be associated with dysregulated cortisol rhythms and consequent clinical exacerbations in bipolar disorders130. This finding provides clear evidence of the link between TSPO, cholesterol binding, and steroid formation under normal and stress conditions. Evolution TSPO is an evolutionary conserved 3.5-billion-year-old protein131. Structural and functional evolution of the translocator protein (18 kDa. TSPO, named for its high tryptophan content and apparent role in the regulation of the transition between photosynthesis and respiration, is the mammalian TSPO orthologue in the photosynthetic bacterium Rhodobacter132 a close
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