3. TSPO role in organ pathology and injury

Changes in TSPO expression have been linked to several pathological conditions, including cancer, endocrine diseases, and neurological diseases [2]. For example, in the normal brain,

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TSPO takes part in mitochondrial ATP production and transport, and is located on cytoplasmic and nuclear membranes and on the outer membrane of mitochondria. TSPO is abundant in metabolically active cells in different organs, such as brain, kidney, and so forth. [2]. TSPO has been also found in other organs and generally is abundant in steroid-secreting tissues. Recently, it has been detected in high abundance in osteoblasts [5]. TSPO interacts with ligands to modulate various molecular cellular activities [5–9] by affecting cell death. TSPO is thought to be involved in mitochondrial cholesterol transport and related to cell death pathways (apoptosis and necrosis) as a functional part of the mitochondrial permeability transition pore (MPTP), along with additional related receptors and protein structures, for example, voltage-dependent anion channel (VDAC) and the adenine nucleotide translocase (ANT) [1, 2]. The existence of functional interconnection between TSPO and MPTP has been challenged recently in studies showing that the MPTP can induce apoptosis and cholesterol transport without the involvement of TSPO [10]. Thus, the exact mechanism of the TSPO involvement in cell death has not been

determined yet, but its functional role in this process is strongly supported [1, 2, 6–8].

Ligands, either endogenous or synthetic, to TSPO, such as protoporphyrin IX (PPIX), PK 11195, Ro5–4864, FGIN-1-27, induce different effects on metabolism and protein expression in human well-differentiated metabolically active cells. For example, Ro5–4864, FGIN-1-27 and PPIX cause similar effects, for example, reducing cellular [18F]-fluorodeoxyglucose ([18F]-FDG) incorporation and parallel decrease in ATP generation [6–8]. The cellular effects of PK 11195 show protective attempts for cellular "detoxification" by increasing the cellular mitochondrial

In general, most of the TSPO ligands affect the cellular function or metabolism in the same general direction, but different specific TSPO ligands have their own unique effects in human cells. Regulation of gene expression via the actions of TSPO ligands on the mitochondrial

The exact mode of action of the specific TSPO ligands is not clear enough and should be further investigated. Due to the evidence of the nonuniform response of cells to the different specific ligands, an attempt to elucidate the role of the TSPO in cellular metabolism and modulation of

Changes in TSPO expression have been linked to several pathological conditions, including cancer, endocrine diseases, and neurological diseases [2]. For example, in the normal brain,

TSPO may form an essential mechanism for the regulation of cellular functions.

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228 Mitochondrial Diseases

2. TSPO ligands

mass (Figure 1) [5].

cell phenotype should be promoted.

3. TSPO role in organ pathology and injury

Figure 1. A: Microscopic image of cells stained by Mitotracker green stain (MTG). Strings of green stained mitochondria are apparent. Confocal microscopy, scale – 20 μ. B: Flow cytometry of cells stained by MTG. The histogram of the mitochondrial mass is shifted showing when exposed to PK 11195 (10<sup>5</sup> M) indicating on increase in the mitochondrial mass in comparison with the unexposed control.

overall TSPO expression is low, and TSPO is mainly found in glia and at very low levels in neurons [9]. But in the abnormal brain, TSPO is mainly expressed in glia, some hypertrophic astrocytes, infiltrating macrophages, and at low levels in neurons.

TSPO expression is upregulated in the injured brain and topographically localized in the inflamed areas. Additionally, in various neuropathologies, that is, gliomas, ischemia, viral encephalitis, neurodegenerative disorders (Parkinson's disease, Huntington's disease, Alzheimer's disease, and amyotrophic lateral sclerosis), local high expression of TSPO is evident [9–11, 12].

Mitochondria are the key regulators of cell survival and death. Mitochondria interact with numerous specific proteins, which are involved in genetic forms of neurodegenerative diseases [5, 9, 11]. When TSPO is a mitochondrial protein, it plays an important role in various cellular pathways related to brain damage and neurodegenerative disease [12].

The potential intracellular mechanisms related to TSPO include Ca++ release, ATP production, reactive oxygen species (ROS) generation, and cytochrome C release from the mitochondria in relation to programmed cell death [7, 13, 14].
