Dataset Information

Mitochondria-associated microRNAs in rat hippocampus following traumatic brain injury.

ABSTRACT: Traumatic brain injury (TBI) is a major cause of death and disability. However, the molecular events contributing to the pathogenesis are not well understood. Mitochondria serve as the powerhouse of cells, respond to cellular demands and stressors, and play an essential role in cell signaling, differentiation, and survival. There is clear evidence of compromised mitochondrial function following TBI; however, the underlying mechanisms and consequences are not clear. MicroRNAs (miRNAs) are small non-coding RNA molecules that regulate gene expression post-transcriptionally, and function as important mediators of neuronal development, synaptic plasticity, and neurodegeneration. Several miRNAs show altered expression following TBI; however, the relevance of mitochondria in these pathways is unknown. Here, we present evidence supporting the association of miRNA with hippocampal mitochondria, as well as changes in mitochondria-associated miRNA expression following a controlled cortical impact (CCI) injury in rats. Specifically, we found that the miRNA processing proteins Argonaute (AGO) and Dicer are present in mitochondria fractions from uninjured rat hippocampus, and immunoprecipitation of AGO associated miRNA from mitochondria suggests the presence of functional RNA-induced silencing complexes. Interestingly, RT-qPCR miRNA array studies revealed that a subset of miRNA is enriched in mitochondria relative to cytoplasm. At 12h following CCI, several miRNAs are significantly altered in hippocampal mitochondria and cytoplasm. In addition, levels of miR-155 and miR-223, both of which play a role in inflammatory processes, are significantly elevated in both cytoplasm and mitochondria. We propose that mitochondria-associated miRNAs may play an important role in regulating the response to TBI.

SUBMITTER: Wang WX

PROVIDER: S-EPMC4346439 | biostudies-literature | 2015 Mar

REPOSITORIES: biostudies-literature

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Mitochondria-associated microRNAs in rat hippocampus following traumatic brain injury.

Wang Wang-Xia WX Visavadiya Nishant P NP Pandya Jignesh D JD Nelson Peter T PT Sullivan Patrick G PG Springer Joe E JE

Experimental neurology 20150103

Traumatic brain injury (TBI) is a major cause of death and disability. However, the molecular events contributing to the pathogenesis are not well understood. Mitochondria serve as the powerhouse of cells, respond to cellular demands and stressors, and play an essential role in cell signaling, differentiation, and survival. There is clear evidence of compromised mitochondrial function following TBI; however, the underlying mechanisms and consequences are not clear. MicroRNAs (miRNAs) are small n ...[more]

PMID: 25562527

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Project description:MicroRNAs (miRNAs) are small non-coding RNA molecules that regulate post-transcriptional gene expression and contribute to all aspects of cellular function. We previously reported that the activities of several mitochondria-enriched miRNAs regulating inflammation (i.e., miR-142-3p, miR-142-5p, and miR-146a) are altered in the hippocampus at 3-12 hours following a severe traumatic brain injury. In the present study, we investigated the temporal expression profile of these inflammatory miRNAs in mitochondria and cytosol fractions at more chronic post-injury times following severe controlled cortical impact injury in rats. In addition, several inflammatory genes were analyzed in the cytosol fractions. The analysis showed that while elevated levels were observed in cytoplasm, the mitochondria-enriched miRNAs, miR-142-3p and miR-142-5p continued to be significantly reduced in mitochondria from injured hippocampi for at least 3 days and returned to near normal levels at 7 days post-injury. Although not statistically significant, miR-146a also remained at reduced levels for up to 3 days following controlled cortical impact injury, and recovered by 7 days. In contrast, miRNAs that are not enriched in mitochondria, including miR-124a, miR-150, miR-19b, miR-155, and miR-223 were either increased or demonstrated no change in their levels in mitochondrial fractions for 7 days. The one exception was that miR-223 levels were reduced in mitochondria at 1 day following injury. No major alterations were observed in sham operated animals. This temporal pattern was unique to mitochondria-enriched miRNAs and correlated with injury-induced changes in mitochondrial bioenergetics as well as expression levels of several inflammatory markers. These observations suggested a potential compartmental re-distribution of the mitochondria-enriched inflammatory miRNAs and may reflect an intracellular mechanism by which specific miRNAs regulate injury-induced inflammatory signaling. To test this, we utilized a novel peptide-based nanoparticle strategy for in vitro and in vivo delivery of a miR-146a mimic as a potential therapeutic strategy for targeting nuclear factor-kappaB inflammatory modulators in the injured brain. Nanoparticle delivery of miR-146a to BV-2 or SH-SY5Y cells significantly reduced expression of TNF receptor-associated factor 6 (TRAF6) and interleukin-1 receptor-associated kinase 1 (IRAK1), two important modulators of the nuclear factor-kappaB (NF-κB) pro-inflammatory pathway. Moreover, injections of miR-146a containing nanoparticles into the brain immediately following controlled cortical impact injury significantly reduced hippocampal TNF receptor-associated factor 6 and interleukin-1 receptor-associated kinase 1 levels. Taken together, our studies demonstrate the subcellular alteration of inflammatory miRNAs after traumatic brain injury and establish proof of principle that nanoparticle delivery of miR-146a has therapeutic potential for modulating pro-inflammatory effectors in the injured brain. All of the studies performed were approved by the University of Kentucky Institutional Animal Care and Usage Committee (IACUC protocol # 2014-1300) on August 17, 2017.

Project description:BACKGROUND:Traumatic brain injury (TBI) has increased in rank among traumatic injuries worldwide. Traumatic brain injury is a serious obstacle given that its complex pathology represents a long-term process. Recently, systems biology strategies such as metabolomics to investigate the multifactorial nature of TBI have facilitated attempts to find biomarkers and probe molecular pathways for its diagnosis and therapy. METHODS:This study included a group of 20 rats with controlled cortical impact and a group of 20 sham rats. We utilized mNSS tests to investigate neurological metabolic impairments on day 1 and day 3. Furthermore, we applied metabolomics and bioinformatics to determine the metabolic perturbation caused by TBI during the acute period in the hippocampus tissue of controlled cortical impact (CCI) rats. Notably, TBI-protein-metabolite subnetworks identified from a database were assessed for associations between metabolites and TBI by the dysregulation of related enzymes and transporters. RESULTS:Our results identified 7 and 8 biomarkers on day 1 and day 3, respectively. Additionally, related pathway disorders showed effects on arginine and proline metabolism as well as taurine and hypotaurine metabolism on day 3 in acute TBI. Furthermore, according to metabolite-protein database searches, 25 metabolite-protein pairs were established as causally associated with TBI. Further, bioinformation indicated that these TBI-associated proteins mainly take part in 5'-nucleotidase activity and carboxylic acid transmembrane transport. In addition, interweaved networks were constructed to show that the development of TBI might be affected by metabolite-related proteins and their protein pathways. CONCLUSION:The overall results show that acute TBI is susceptible to metabolic disorders, and the joint metabolite-protein network analysis provides a favorable prediction of TBI pathogenesis mechanisms in the brain. The signatures in the hippocampus might be promising for the development of biomarkers and pathways relevant to acute TBI and could further guide testable predictions of the underlying mechanism of TBI.

Dataset Information

Mitochondria-associated microRNAs in rat hippocampus following traumatic brain injury.

Publications

Mitochondria-associated microRNAs in rat hippocampus following traumatic brain injury.

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