Nurr1 exacerbates cerebral ischemia-reperfusion injury via modulating YAP-INF2-mitochondrial fission pathways
2018
Nurr1, a nuclear transcription factor, has been linked to ischemia-reperfusion injury (IRI) in heart and kidney via modulating mitochondrial homeostasis. However, its role in cerebral ischemia-reperfusion has not been defined. In the present study, we found that cerebral IRI significantly increased the expression of Nurr1 and genetic ablation of Nurr1 attenuated the infarction area and reduced the neuron apoptosis under brain IRI burden. Functional studies have demonstrated that Nurr1 induced neuron death via activating mitochondrial fission. Aberrant mitochondrial fission promoted mitochondrial membrane potential reduction, evoked cellular oxidative stress and activated caspase-9-dependent mitochondrial apoptotic pathway. Interestingly, Nurr1 deletion alleviated fission-mediated mitochondrial damage, sustaining mitochondrial homeostasis and favoring neuron survival. Further, we found that Nurr1 deletion modulated mitochondrial fission via preventing INF2 upregulation in a manner dependent on YAP pathways. Either pharmacological blockade of YAP pathway or overexpression of INF2 abrogated the inhibitory effect of Nurr1 deletion on mitochondrial fission, leading to neuron death via mitochondrial apoptosis. Altogether, our results report that the pathogenesis of cerebral ischemia-reperfusion injury is associated with Nurr1 upregulation followed by augmented mitochondrial fission via an abnormal YAP-INF2 pathways.
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