Sam50 exerts neuroprotection by maintaining the mitochondrial structure during experimental cerebral ischemia/reperfusion injury in rats.

Abstract

To investigate the role of Sam50, a barrel protein on the surface of the mitochondrial outer membrane, in cerebral ischemia-reperfusion (I/R) injury and its underlying mechanisms. A middle cerebral artery occlusion/reperfusion (MCAO/R) model in adult male Sprague-Dawley rats was established in vivo, and cultured neurons were exposed to oxygen-glucose deprivation/reoxygenation (OGD/R) to simulate I/R injury in vitro. Lentiviral vector encoding Sam50 or Sam50 shRNA was constructed and administered to rats by intracerebroventricular injection to overexpress and knockdown Sam50, respectively. First, after MCAO/R induction, the mitochondrial structure was damaged, and Sam50 protein levels were increased responsively both in vivo and in vitro. Then, it was found that Sam50 overexpression could reduce infarction size, inhibit neuronal cell death, improve neurobehavioral disability, protect mitochondrial structure integrity, and ameliorate mitochondrial dysfunction, which was induced by I/R injury both in vivo and in vitro. However, Sam50 downregulation showed the opposite results and aggravated I/R injury by inducing neuronal cell death, neurobehavioral disability, and mitochondrial dysfunction. Moreover, we found that the interaction between Sam50 and Mic19 was broken off after OGD/R, showing that the Sam50-Mic19-Mic60 axis was breakage in neurons, which would be a reason for mitochondrial structure and function abnormalities induced by I/R injury. Sam50 played a vital role in the protection of neurons and mitochondria in cerebral I/R injury, which could be a novel target for mitochondrial protection and ameliorating I/R injury.