The Mitochondria-Associated ER Membranes Are Novel Subcellular Locations Enriched for Inflammatory-Responsive MicroRNAs

Wang-Xia Wang,Joe E Springer,Paresh Prajapati,Peter T Nelson

doi:10.1007/s12035-020-01937-y

Wang-Xia Wang, Joe E Springer + Show 2 more

Open Access

https://doi.org/10.1007/s12035-020-01937-y

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Journal: Molecular Neurobiology	Publication Date: May 25, 2020
Citations: 23	License type: open-access

Affiliation: University of Kentucky

Abstract

The mitochondria-associated endoplasmic reticulum (ER) membranes (MAMs) are specific ER domains that contact the mitochondria and function to facilitate communication between ER and mitochondria. Disruption of contact between the mitochondria and ER is associated with a variety of pathophysiological conditions including neurodegenerative diseases. Considering the many cellular functions of MAMs, we hypothesized that MAMs play an important role in regulating microRNA (miRNA) activity linked to its unique location between mitochondria and ER. Here we present new findings from human and rat brains indicating that the MAMs are subcellular sites enriched for specific miRNAs. We employed subcellular fractionation and TaqMan® RT-qPCR miRNA analysis to quantify miRNA levels in subcellular fractions isolated from male rat brains and six human brain samples. We found that MAMs contain a substantial number of miRNAs and the profile differs significantly from that of cytosolic, mitochondria, or ER. Interestingly, MAMs are particularly enriched in inflammatory-responsive miRNAs, including miR-146a, miR-142-3p, and miR-142-5p in both human and rat brains; miR-223 MAM enrichment was observed only in human brain samples. Further, mitochondrial uncoupling or traumatic brain injury in male rats resulted in the alteration of inflammatory miRNA enrichment in the isolated subcellular fractions. These observations demonstrate that miRNAs are distributed differentially in organelles and may re-distribute between organelles and the cytosol in response to cellular stress and metabolic demands.

Highlights

Many physiological functions are regulated via the mitochondria-associated endoplasmic reticulum (ER) membranes (MAMs)
We examined the subcellular distribution pattern of these miRNAs in cortical samples of rats treated with a mitochondrial uncoupling agent and in rats subjected to a severe TBI, which is associated with a rapid compromise in mitochondrial function
We show here for the first time that mitochondria-associated ER membranes (MAMs) are subcellular locations for miRNAs in rat and human cerebral cortex, and this cellular domain contains several inflammatory-responsive miRNAs that are highly enriched in the mitochondria

Summary

Introduction

Many physiological functions are regulated via the mitochondria-associated ER membranes (MAMs). The MAMs are specific ER domains that tether the mitochondria to regions of the ER and play a role in lipid synthesis, calcium transport and homeostasis, mitochondria dynamics, and regulating autophagosome and inflammasome formation [1,2,3,4,5,6,7,8,9,10,11,12]. It is not surprising that disturbances in MAM-regulated biological processes affect a wide range of normal cellular processes. There are many unanswered questions as to how the mitochondria and ER physiological processes are regulated in relation to MAMs, and what additional functions may be attributed to this cell domain. We propose a previously undescribed feature of MAMs in the brain, related to the presence of microRNAs (miRNAs)

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