%0 Figure %A Wei, Jialiang %A Wu, Xiuquan %A Luo, Peng %A Yue, Kangyi %A Yu, Yang %A Pu, Jingnan %A Zhang, Lei %A Dai, Shuhui %A Han, Donghui %A Fei, Zhou %D 2019 %T Image_1_Homer1a Attenuates Endoplasmic Reticulum Stress-Induced Mitochondrial Stress After Ischemic Reperfusion Injury by Inhibiting the PERK Pathway.TIF %U https://frontiersin.figshare.com/articles/figure/Image_1_Homer1a_Attenuates_Endoplasmic_Reticulum_Stress-Induced_Mitochondrial_Stress_After_Ischemic_Reperfusion_Injury_by_Inhibiting_the_PERK_Pathway_TIF/7849589 %R 10.3389/fncel.2019.00101.s001 %2 https://frontiersin.figshare.com/ndownloader/files/14615807 %K ischemic stroke %K homer1a %K mitochondrial dysfunction %K endoplasmic reticulum stress %K PERK kinase %X

Homer1a is the short form of a scaffold protein that plays a protective role in many forms of stress. However, the role of Homer1a in cerebral ischemia/reperfusion (I/R) injury and its potential mechanism is still unknown. In this study, we found that Homer1a was upregulated by oxygen and glucose deprivation (OGD) and that overexpression of Homer1a alleviated OGD-induced lactate dehydrogenase (LDH) release and cell death in cultured cortical neurons. After OGD treatment, the overexpression of Homer1a preserved mitochondrial function, as evidenced by less cytochrome c release, less reactive oxygen species (ROS) production, less ATP and mitochondrial membrane potential (MMP) loss, less caspase-9 activation, and inhibition of endoplasmic reticulum (ER) stress confirmed by the decreased expression of phosphate-PKR-like ER Kinase (p-PERK)/PERK and phosphate- inositol-requiring enzyme 1 (p-IRE1)/IRE1 and immunofluorescence (IF) staining. In addition, mitochondrial protection of Homer1a was blocked by the ER stress activator Tunicamycin (TM) with a re-escalated ROS level, increasing ATP and MMP loss. Furthermore, Homer1a overexpression-induced mitochondrial stress attenuation was significantly reversed by activating the PERK pathway with TM and p-IRE1 inhibitor 3,5-dibromosalicylaldehyde (DBSA), as evidenced by increased cytochrome c release, increased ATP loss and a higher ROS level. However, activating the IRE1 pathway with TM and p-PERK inhibitor GSK2656157 showed little change in cytochrome c release and exhibited a moderate upgrade of ATP loss and ROS production in neurons. In summary, these findings demonstrated that Homer1a protects against OGD-induced injury by preserving mitochondrial function through inhibiting the PERK pathway. Our finding may reveal a promising target of protecting neurons from cerebral I/R injury.

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