TSPO: kaleidoscopic 18-kDa amid biochemical pharmacology, control and targeting of mitochondria

Abstract

The 18-kDa translocator protein (TSPO) localizes in the outer mitochondrial membrane (OMM) of cells and is readily up-regulated under various pathological conditions such as cancer, inflammation, mechanical lesions and neurological diseases. Able to bind with high affinity synthetic and endogenous ligands, its core biochemical function resides in the translocation of cholesterol into the mitochondria influencing the subsequent steps of (neuro-)steroid synthesis and systemic endocrine regulation. Over the years, however, TSPO has also been linked to core cellular processes such as apoptosis and autophagy. It interacts and forms complexes with other mitochondrial proteins such as the voltage-dependent anion channel (VDAC) via which signalling and regulatory transduction of these core cellular events may be influenced. Despite nearly 40 years of study, the precise functional role of TSPO beyond cholesterol trafficking remains elusive even though the recent breakthroughs on its high-resolution crystal structure and contribution to quality-control signalling of mitochondria. All this along with a captivating pharmacological profile provides novel opportunities to investigate and understand the significance of this highly conserved protein as well as contribute the development of specific therapeutics as presented and discussed in the present review.

The pharmacological regulation of cellular mitophagy

“…55 These include modulators of epigenetic mechanisms, such as histone deacetylase and bromodomain inhibitors, and small molecule inhibitors of cholesterol biosynthesis, such as mevastatin and fluvastatin. 56 Interestingly, the JNK inhibitor SR3306, another promising lead identified in the same study, seems to enhance mitochondrial quality control in a cell-based model of mitochondrial stress induced by the accumulation of misfolded ΔOTC (truncated ornithine transcarbamylase).…”

“…TSPO levels are elevated in pathological conditions associated with mitophagy defects, highlighting its pharmacological targeting as a suitable strategy to therapeutically activate mitophagy. 56 Though, the limited selectivity of the most widely used TSPO ligands may restrict the options for its targeting in this context, 56,57 the recent elucidation of TSPOs three-dimensional structure shall facilitate the design of improved chemicals to shed light on the protein's role in the modulation of mitophagy. 56 The ubiquitin specific peptidase 30 (USP30) is a mitochondrion-localized deubiquitylase known for its role in the regulation of mitochondrial morphology.…”

“…56 Though, the limited selectivity of the most widely used TSPO ligands may restrict the options for its targeting in this context, 56,57 the recent elucidation of TSPOs three-dimensional structure shall facilitate the design of improved chemicals to shed light on the protein's role in the modulation of mitophagy. 56 The ubiquitin specific peptidase 30 (USP30) is a mitochondrion-localized deubiquitylase known for its role in the regulation of mitochondrial morphology. 58,59 USP30 antagonizes Parkin-driven mitophagy by removing poly-ubiquitin chains from …”

Flutriciclamide (18F-GE180) PET: First-in-Human PET Study of Novel Third-Generation In Vivo Marker of Human Translocator Protein

“…Under normal conditions, microglial cells are in a state of surveillance with elongated processes. During injury or neurodegenerative processes, microglial cells become activated; the activated state is mirrored by upregulation of translocator protein (TSPO) (1,2). PET with TSPO-specific ligands provides an in vivo technique to detect microglial activation (3).…”

Current status and future perspectives: TSPO in steroid neuroendocrinology

“…Investigating how the field of steroid endocrinology got to this point, we have carefully reappraised previous studies from 25 years of TSPO research, and examined their limitations that led to the inaccurate association of TSPO and steroidogenesis in a recent review (Selvaraj et al 2015). Nevertheless, as this proposition of TSPO and mitochondrial cholesterol import had pervaded the scientific literature across multiple fields connected in different organ systems, some have had difficulty in reconciling these differences , and others not directly working on mechanisms of steroid production are likewise unable to do so (Campanella 2015, Gatliff & Campanella 2016. This is mainly because removal of TSPO from the steroid production equation has left the field without an explanation for its high expression in steroidogenic tissues and the different effects mediated by TSPO-binding chemicals/drugs.…”