120 Chapter 5 living relative of mitochondria56. Detailed evolutionary studies indicated that the Tspo gene family has been expanded by gene duplications from a bacterial environmental sensor or signal transducer to a functional bioregulator adapted to organism-, tissue-, cell-, and organelle-specific needs. Interestingly, the mammalian protein is able to rescue the phenotypes of bacterial TspO KO suggesting a conserved function133 and that one compensates for the loss of oxygen sensing function that occurs when the other is depleted. An additional Tspo family member, Tspo2, has been characterized134. Comparative analysis of Tspo1, the first family member to be identified, and Tspo2 structure and function indicates that TSPO2 was characterized by the loss of diagnostic drug ligand binding, but retention of cholesterol binding properties, and is involved in cholesterol redistribution during erythropoiesis134. Whether there are additional family members in mammals or humans remains to be determined. However, the highly conserved sequence would seem to indicate that such expansion in members was not needed to support the rich expansion of cellular functions. Pharmacological and structural evidence supports TSPO functioning in tetrapyrrole biosynthesis, porphyrin transport, heme metabolism, cholesterol transport/trafficking, steroid formation, control of ROS levels, and the protection of mitochondria from free radical damage. All evolutionarily conserved functions are linked to mitochondria and affected by changes in mitochondrial membrane potential, a function dependent on the presence of TSPO. Few years ago, we proposed that the central role of TSPO throughout evolution is in oxygen-mediated metabolism. This central function has diversified roles in tissue- and cellspecific signalling, metabolism, cholesterol trafficking, immunological responses, apoptosis, steroid synthesis, and host-defence response to disease and injury, all oxygen-mediated pathways21,131. Summary TSPO is a multifunctional protein involved in a wide array of cellular functions that are essential for human health. Its central location in the mitochondria, a multifunctional organelle itself, underscores its importance at the crossroads of critical homeostatic pathways. Its evolutionarily conserved sequence also supports its cellular significance. As we continue to elucidate the intricacies of the role of TSPO in health and disease, we will have the opportunity to identify new therapeutic and diagnostic targets that will have significant impact in the near and long term. TSPOcellorigininwild-typeandpreclinicalmodelsofneurological disease Wild-type The density and cell origin of TSPO were assessed in the mouse brain. The specificity of TSPO staining was confirmed using a TSPO-deficient strain135. Two major findings were reported: TSPO is not homogeneously expressed in the various brain regions and the cell origin also varies across brain regions. The cerebellum shows high levels of TSPO staining as does the choroid plexus and the ependyma of the ventricular system. In addition, TSPO expression in the white matter is generally higher than in the grey matter. Regarding the cell origin of TSPO, in the cortex, astrocytes and microglia lack the constitutive TSPO expression observed in white matter. In contrast, in the hippocampus, TSPO is predominantly present in the
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