Mitofusin 2 Mediates the Protective Effect of NR6A1 Silencing Against Neuronal Injury in Experimental Stroke Models.

Abstract

An abnormal increase in the expression of nuclear receptor subfamily 6 group A member 1 (NR6A1) in the hippocampus has been reported to result in depressive-like behavior in mice. However, the role of NR6A1 in the progression of neuronal death induced by ischemic stroke remains unknown. In this study, we observed an increase in NR6A1 in neurons in both in vivo and in vitro cerebral ischemic models. We found that knocking down NR6A1 in HT-22 neuronal cells subjected to oxygen-glucose deprivation/reoxygenation (OGD/R) attenuated mitochondrial dysfunction and endoplasmic reticulum (ER) stress. Conversely, NR6A1 overexpression exacerbated neuronal damage following OGD/R. NR6A1 hindered the transcription of mitonfusin 2 (MFN2), leading to a decrease in its expression. In contrast, MFN2 conferred the protective effect of NR6A1 silencing against both mitochondrial dysfunction and ER stress. In addition, NR6A1 silencing also attenuated brain infarction, ER stress, neuronal apoptosis, and loss of MFN2 in mice subjected to middle cerebral artery occlusion/reperfusion. These findings indicate that NR6A1 is a promising target for the treatment of neuronal death following cerebral ischemia. Furthermore, these results confirm the involvement of MFN2 in the effects of NR6A1 silencing. Therefore, targeting NR6A1 has potential as a viable strategy for the treatment of ischemic stroke.