Critical role of translocator protein (TSPO) in neuronal mitochondrial dysfunction and mental stress-exacerbated ischemic injury following stroke.

Stroke remains the second leading cause of death and disability globally, yet the contribution of depressive disorders and psychological stress to stroke outcomes is often overlooked. Emerging evidence suggests that mitochondrial dysfunction may mediate this relationship. So this study aims to investigate the potential causal role of mental stress in exacerbating ischemic brain injury and identify mitochondrial proteins that contribute to this interaction. In the study, the chronic restraint stress (CRS) model was applied, and mice were subjected to 45 min of middle cerebral artery occlusion (MCAO) followed by 24 h or 48 h of reperfusion. Translocator protein (TSPO) antagonist PK11195 was injected intraperitoneally every day during CRS. Brain injury was determined by infarct volumes, cell apoptosis, Fas expression, release of lactate dehydrogenase (LDH), and reactive oxygen species (ROS). Protein expression was analyzed by Western blot. In SH-SY5Y cells, cell viability was assessed after oxygen-glucose deprivation/reoxygenation (OGD/R). Mitochondrial function was assessed after transfecting a TSPO overexpression vector (pLV-TSPO) or treated with PK11195. The results shown that CRS induced depressive-like behaviors and increased brain injury after stroke in association with impaired mitochondrial function. TSPO was elevated by CRS, and TSPO induced voltage-dependent anion channel (VDAC) phosphorylation through interaction with acyl-CoA binding domain containing 3 (ACBD3), which was reversed by PK11195. In SH-SY5Y cells, TSPO overexpression led to mitochondrial dysfunction, which was reversed by PK11195. In conclusion, the study supports a central role for TSPO in linking mental stress to adverse stroke outcomes and points to its potential as a therapeutic target for cerebrovascular health.