4.5 Article

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

期刊

JOURNAL OF NEUROTRAUMA
卷 39, 期 7-8, 页码 560-576

出版社

MARY ANN LIEBERT, INC
DOI: 10.1089/neu.2021.0347

关键词

apoptosis; endoplasmic reticulum-mitochondria coupling; endoplasmic reticulum stress; traumatic brain injury; unfolded protein response

资金

  1. Tianjin Neurological Institute
  2. Department of Neurosurgery, Tianjin Medical University General Hospital

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Cellular homeostasis requires critical communications between the endoplasmic reticulum (ER) and mitochondria to maintain cell viability. Disruption of this communication during acute traumatic brain injury (TBI) may lead to neuronal and supporting cell damage. In this study, we found that severe TBI induced significant reorganizations of mitochondria-associated ER membranes (MAMs) within the first 24 hours post-injury. This enhanced ER-mitochondrion coupling correlated closely with changes in Ca2+ regulatory proteins, ROS production, ER stress, UPR levels, and proinflammatory cytokine release. Silencing the gene for the ER-mitochondrion tethering factor PACS2 improved neurological function in sTBI mice. These findings suggest that modulating ER-mitochondrion crosstalk could be a novel therapeutic strategy for sTBI.
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 Ca2+ regulatory proteins (inositol 1,4,5-trisphosphate receptor type 1 [IP3R1], voltage-dependent anion channel 1 [VDAC1], glucose-regulated protein 75 [GRP75], Sigma 1 receptor [Sigma-1R]), production of ROS, degree of ER stress, levels of UPR, and release of proinflammatory cytokines. Further, the neurological function of sTBI mice was significantly improved by silencing the gene for the ER-mitochondrion tethering factor PACS2, restoring the IP3R1-GRP75-VDAC1 axis of Ca2+ regulation, alleviating mitochondria-derived oxidative stress, suppressing inflammatory response through the PERK/eIF2 alpha/ATF4/CHOP pathway, and inhibiting ER stress and associated apoptosis. These results indicate that dysfunctional ER-mitochondrion coupling might be primarily involved in the neuronal apoptosis and neurological deficits, and modulating the ER-mitochondrion crosstalk might be a novel therapeutic strategy for sTBI.

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