Dataset Information

Intertwined Relation between the Endoplasmic Reticulum and Mitochondria in Ischemic Stroke.

ABSTRACT: In ischemic stroke (IS), accumulation of the misfolded proteins in the endoplasmic reticulum (ER) and mitochondria-induced oxidative stress (OS) has been identified as the indispensable inducers of secondary brain injury. With the increasing recognition of an association between ER stress and OS with ischemic stroke and with the improved understanding of the underlying molecular mechanism, novel targets for drug therapy and new strategies for therapeutic interventions are surfacing. This review discusses the molecular mechanism underlying ER stress and OS response as both causes and consequences of ischemic stroke. We also summarize the latest advances in understanding the importance of ER stress and OS in the pathogenesis of ischemic stroke and discuss potential strategies and clinical trials explicitly aiming to restore mitochondria and ER dynamics after IS.

SUBMITTER: Peng J

PROVIDER: S-EPMC9072026 | biostudies-literature | 2022

REPOSITORIES: biostudies-literature

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Intertwined Relation between the Endoplasmic Reticulum and Mitochondria in Ischemic Stroke.

Peng Jianhua J Ghosh Dipritu D Pang Jinwei J Zhang Lifang L Yin Shigang S Jiang Yong Y

Oxidative medicine and cellular longevity 20220428

In ischemic stroke (IS), accumulation of the misfolded proteins in the endoplasmic reticulum (ER) and mitochondria-induced oxidative stress (OS) has been identified as the indispensable inducers of secondary brain injury. With the increasing recognition of an association between ER stress and OS with ischemic stroke and with the improved understanding of the underlying molecular mechanism, novel targets for drug therapy and new strategies for therapeutic interventions are surfacing. This review ...[more]

PMID: 35528523

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Project description:BackgroundProlonged cellular activity may overload cell function, leading to high rates of protein synthesis and accumulation of misfolded or unassembled proteins, which cause endoplasmic reticulum (ER) stress and activate the unfolded protein response (UPR) to re-establish normal protein homeostasis. Previous molecular work has demonstrated that sleep deprivation (SD) leads to ER stress in neurons, with a number of ER-specific proteins being upregulated to maintain optimal cellular proteostasis. It is still not clear which cellular processes activated by sleep deprivation lead to ER- stress, but increased cellular metabolism, higher request for protein synthesis, and over production of oxygen radicals have been proposed as potential contributing factors. Here, we investigate the transcriptional and ultrastructural ER and mitochondrial modifications induced by sleep loss.ResultsWe used gene expression analysis in mouse forebrains to show that SD was associated with significant transcriptional modifications of genes involved in ER stress but also in ER-mitochondria interaction, calcium homeostasis, and mitochondrial respiratory activity. Using electron microscopy, we also showed that SD was associated with a general increase in the density of ER cisternae in pyramidal neurons of the motor cortex. Moreover, ER cisternae established new contact sites with mitochondria, the so-called mitochondria associated membranes (MAMs), important hubs for molecule shuttling, such as calcium and lipids, and for the modulation of ATP production and redox state. Finally, we demonstrated that Drosophila male mutant flies (elav > linker), in which the number of MAMs had been genetically increased, showed a reduction in the amount and consolidation of sleep without alterations in the homeostatic sleep response to SD.ConclusionsWe provide evidence that sleep loss induces ER stress characterized by increased crosstalk between ER and mitochondria. MAMs formation associated with SD could represent a key phenomenon for the modulation of multiple cellular processes that ensure appropriate responses to increased cell metabolism. In addition, MAMs establishment may play a role in the regulation of sleep under baseline conditions.

Project description:BackgroundNeuronal apoptosis, which is the primary pathological transform of cerebral injury following ischemic stroke (IS), is considered to be induced by endoplasmic reticulum stress (ERS) by numerous reports. However, ERS biomarkers in IS have not been fully identified yet. Consequently, the present study is aimed at exploring potential blood biomarkers by investigating the molecular mechanisms of ERS promoting neuronal apoptosis following IS development.MethodsA comprehensive analysis was performed with two free-accessible whole-blood datasets (GSE16561 and GSE37587) from the Gene Expression Omnibus database. Genetic information from 107 IS and 24 healthy controls was employed to analyze the differentially expressed genes (DEGs). Genes related to ERS (ERS-DEGs) were identified from the analysis. Enrichment analyses were performed to explore the biofunction and correlated signal pathways of ERS-DEGs. Protein-protein interaction (PPI) network and immune correlation analyses were performed to identify the hub genes along with their correspondent expressions and functions, all of which contributed to incremental diagnostic values.ResultsA total of 60 IS-related DEGs were identified, of which 27 genes were confirmed as ERS-DEGs. GO and KEGG enrichment analysis corroborated that upregulated ERS-DEGs were principally enriched in pathways related to immunity, including neutrophil activation and Th17 cell differentiation. Moreover, the GSEA and GSVA indicated that T cell-related signal pathways were the most considerably immune pathways for ERS-DEG enrichment. A total of 10 hub genes were filtered out via the PPI network analysis. Immune correlation analysis confirmed that the expression of hub genes is associated with immune cell infiltration.ConclusionsBy integrating and analyzing the two gene expression data profiles, it can be inferred that ERS may be involved in the development of neuronal apoptosis following IS via immune homeostasis. The identified hub genes, which are associated with immune cell infiltration, may serve as potential biomarkers for relative diagnosis and therapy.

Dataset Information

Intertwined Relation between the Endoplasmic Reticulum and Mitochondria in Ischemic Stroke.

Publications

Intertwined Relation between the Endoplasmic Reticulum and Mitochondria in Ischemic Stroke.

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