Dysfunctional Endoplasmic Reticulum-Mitochondrion Coupling Is Associated with Endoplasmic Reticulum Stress-Induced Apoptosis and Neurological Deficits in a Rodent Model of Severe Head Injury

作者：Xin Chen, Liang Mi, Gang Gu, Xiangliang Gao, Xiangliang Gao, Mingming Shi, Yan Chai, Fanglian Chen, Weidong Yang, Jianning Zhang · 发表于：Journal of Neurotrauma · 年份：2022 · DOI：10.1089/neu.2021.0347 · 被引用次数：52 · 研究领域：Mitochondrial Function and Pathology、Endoplasmic Reticulum Stress and Disease、Heme Oxygenase-1 and Carbon Monoxide

Cellular homeostasis requires critical communications between the endoplasmic reticulum (ER) and mitochondria to maintain the viability of cells. This communication is mediated and maintained by the mitochondria-associated membranes and may be disrupted during acute traumatic brain injury (TBI), leading to structural and functional damage of neurons and supporting cells. To test this hypothesis, we subjected male C57BL/6 mice to severe TBI (sTBI) using a controlled cortical impact device. We analyzed the physical ER-mitochondrion contacts in the perilesional cortex using transmission electron microscopy, Western blot, and immunofluorescence. We specifically measured changes in the production of reactive oxygen species (ROS) in mitochondria, the unfolded protein response (UPR), the neuroinflammatory response, and ER stress-mediated apoptosis in the traumatic injured cerebral tissue. A modified neurological severity score was used to evaluate neurological function in the sTBI mice. We found that sTBI induced significant reorganizations of mitochondria-associated ER membranes (MAMs) in the cerebral cortex within the first 24 h post-injury. This ER-mitochondrion coupling was enhanced, reaching its peak level at 6 h post-sTBI. This enhanced coupling correlated closely with increases in the expression of the Ca 2+ regulatory proteins (inositol 1,4,5-trisphosphate receptor type 1 [IP 3 R 1 ], voltage-dependent anion channel 1 [VDAC1], glucose-regulated protein 75 [GRP75], Sigma 1 re...