Abstract
Ischemic stroke results in severe brain damage and remains one of the leading causes of death and disability worldwide. Effective neuroprotective therapies are needed to reduce brain damage resulting from ischemic stroke. Mitochondria are crucial for cellular energy production and homeostasis. Modulation of mitochondrial function mediates neuroprotection against ischemic brain damage. Dynamin-related protein 1 (Drp1) and parkin play a key role in regulating mitochondrial dynamics. They are potential therapeutic targets for neuroprotection in ischemic stroke. Protective effects of parkin-Drp1 pathway on mitochondria were assessed in a cellular ischemia-reperfusion injury model. Mouse neuroblastoma Neuro2a (N2a) cells were subjected to oxygen-glucose deprivation/reperfusion (OGDR) insult. OGDR induces mitochondrial fragmentation. The expression of Drp1 protein is increased after OGDR insult, while the parkin protein level is decreased. The altered protein level of Drp1 after OGDR injury is mediated by parkin through ubiquitin proteasome system (UPS). Drp1 depletion protects against OGDR induced mitochondrial damage and apoptosis. Meanwhile, parkin overexpression protects against OGDR induced apoptosis and mitochondrial dysfunction, which is attenuated by increased expression of Drp1. Our data demonstrate that parkin protects against OGDR insult through promoting degradation of Drp1. This neuroprotective potential of parkin-Drp1 pathway against OGDR insult will pave the way for developing novel neuroprotective agents for cerebral ischemia-reperfusion related disorders.
Highlights
Mitochondria, the power house of the cell, participate in many essential cellular functions, including energy production, ion homeostasis, inflammation, apoptotic cell death, and calcium signaling
To explore whether mitochondrial fragmentation occurs in N2a cells upon oxygen-glucose deprivation/reperfusion (OGDR) insult, we used immunofluorescent staining to evaluate its temporal profiles (Figure 1)
We further investigated the regulatory effect of parkin on dynamin-related protein 1 (Drp1) expression after OGDR insult. siRNA-mediated knockdown of parkin expression was performed in mouse N2a cells
Summary
Mitochondria, the power house of the cell, participate in many essential cellular functions, including energy production, ion homeostasis, inflammation, apoptotic cell death, and calcium signaling. Change in mitochondrial mass and function has been linked with multiple diseases, including cerebral ischemia. Mitochondrial dysfunction is the most fundamental mechanism of cell damage in cerebral ischemiareperfusion injury, which involves multiple independently fatal terminal pathways in the mitochondria. Drp is required for functionally active mitochondria, and supplementing with ATP can restore the defects induced by Drp suppression [5]. On the basis of previous findings, we presumed that parkin and Drp would exert neuroprotective effect on cerebral ischemia/reperfusion that occurred in stroke. We found that Drp depletion protects against OGDR induced mitochondrial damage and apoptosis. Overexpression of parkin protects against OGDR induced apoptosis and mitochondrial dysfunction, which is blocked by upregulation of Drp. Parkin-Drp pathway represents a novel therapeutic target for treatment of a myriad of disorders related to cerebral ischemia-reperfusion injury
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