Functional role of translocator protein and its ligands in ocular diseases (Review)

Abstract

The 18 kDa translocator protein (TSPO) is an essential outer mitochondrial membrane protein that is responsible for mitochondrial transport, maintenance of mitochondrial homeostasis and normal physiological cell function. The role of TSPO in the pathogenesis of ocular diseases is a growing area of interest. More notably, TSPO exerts positive effects in regulating various pathophysiological processes, such as the inflammatory response, oxidative stress, steroid synthesis and modulation of microglial function, in combination with a variety of specific ligands such as 1‑(2‑chlorophenyl‑N‑methylpropyl)‑3‑isoquinolinecarboxamide, 4'‑chlorodiazepam and XBD173. In the present review, the expression of TSPO in ocular tissues and the functional role of TSPO and its ligands in diverse ocular diseases was discussed.

Keywords: TSPO; ligand; ocular diseases.

Figure 1.

Diagram summarizing the key functions of TSPO and TSPO ligands. TSPO is located in the OMM. TSPO reduces mitophagy and is a regulator of multiple mitochondrial functions including mitochondrial respiration, membrane potential, energy homeostasis and quality control. TSPO controls signaling pathways between mitochondria and the nucleus and thereby affects nuclear gene expression. TSPO is involved in the cholesterol transport from the OMM to the IMM. The close apposition of TSPO and mPTP complexes enables TSPO to regulate the function of mPTP, thereby affecting Ca²⁺ transport across the OMM and maintaining Ca²⁺ homeostasis. TSPO ligands modulate TSPO and promote cell steroidogenesis, downregulate cell inflammatory cytokine expression, decrease ROS production as well as induce the switching of microglia from the active state to favor the resting state. TSPO ligands reduce cytochrome c release from mitochondria to the cytoplasm, thereby inhibiting the mitochondrial apoptosis pathway. OMM, outer mitochondrial membrane; IMM, inner mitochondrial membrane; VDAC, voltage-dependent anion channel; ANT, adenine nucleotide translocase; CypD, cyclophilin D; mPTPs, mitochondrial permeability transition pores; ROS, reactive oxygen species; TSPO, translocator protein; COX-2, cyclooxygenase-2; TNF-α, tumor necrosis factor-α; IL, interleukin; CCL2, C-C motif chemokine receptor-2.

Figure 2.

Affected areas or cell types associated with TSPO in various ocular diseases. TSPO, translocator protein; AMD, age-related macular degeneration; DR, diabetic retinopathy; AlloP, allopregnanolone; CNV, choroidal neovascularization; NOX1, NADPH oxidase 1; ROS, reactive oxygen species; RPE, retinal pigment epithelium.