miR-19-3p /GRSF1/COX1 axis attenuates early brain injury via maintaining mitochondrial function after subarachnoid haemorrhage

Abstract

Background Guanine-rich RNA sequence binding factor 1 (GRSF1) is an RNA-binding protein, which is eventually localised to mitochondria and promotes the translation of cytochrome C oxidase 1 (COX1) mRNA. However, the role of the miR-19-3 p/GRSF1/COX1 axis has not been investigated in an experimental subarachnoid haemorrhage (SAH) model. Thus, we investigated the role of the miR-19-3 p/GRSF1/COX1 axis in a SAH-induced early brain injury (EBI) course. Methods Primary neurons were treated with oxyhaemoglobin (OxyHb) to simulate in vitro SAH. The rat SAH model was established by injecting autologous arterial blood into the optic chiasma cisterna. The GRSF1 level was downregulated or upregulated by treating the rats and neurons with lentivirus- GRSF1 shRNA (Lenti- GRSF1 shRNA) or lentivirus- GRSF1 (Lenti- GRSF1 ). Results The miR-19-3 p level was upregulated and the protein levels of GRSF1 and COX1 were both downregulated in SAH brain tissue. GRSF1 silence decreased and GRSF1 overexpression increased the protein levels of GRSF1 and COX1 in primary neurons and brain tissue, respectively. Lenti- GRSF1 shRNA aggravated, but Lenti- GRSF1 alleviated, the indicators of neuronal injury and neurological impairment in both in vitro and in vivo SAH conditions. In addition, miR-19-3 p mimic reduced the protein levels of GRSF1 and COX1 in cultured neurons while miR-19-3 p inhibitor increased them. More importantly, Lenti- GRSF1 significantly relieved mitochondrial damage of neurons exposed to OxyHb or induced by SAH and was beneficial to maintaining mitochondrial integrity. Lenti- GRSF1 shRNA treatment, conversely, aggravated mitochondrial damage in neurons. Conclusion The miR-19-3 p/GRSF1/COX1 axis may serve as an underlying target for inhibiting SAH-induced EBI by maintaining mitochondrial integrity.