Depletion of Mitochondrial Components from Extracellular Vesicles Secreted from Astrocytes in a Mouse Model of Fragile X Syndrome.

Byung Geun Ha,Yu-Jin Jang,Ju-Yeon Choi,Tae-Shin Park,Sung-Jin Jeong,Jung-Yoon Heo,Woo Young Jang

doi:10.3390/ijms22010410

Abstract

Mitochondrial dysfunction contributes to neurodegenerative diseases and developmental disorders such as Fragile X syndrome (FXS). The cross-talk between mitochondria and extracellular vesicles (EVs) suggests that EVs may transfer mitochondrial components as intermediators for intracellular communication under physiological and pathological conditions. In the present study, the ability of EVs to transfer mitochondrial components and their role in mitochondrial dysfunction in astrocytes were examined in the brains of Fmr1 knockout (KO) mice, a model of FXS. The amounts of mitochondrial transcription factor NRF-1, ATP synthases ATP5A and ATPB, and the mitochondrial membrane protein VDAC1 in EVs were reduced in cerebral cortex samples and astrocytes from Fmr1 KO mice. These reductions correspond to decreased mitochondrial biogenesis and transcriptional activities in Fmr1 KO brain, along with decreased mitochondrial membrane potential (MMP) with abnormal localization of vimentin intermediate filament (VIF) in Fmr1 KO astrocytes. Our results suggest that mitochondrial dysfunction in astrocytes is associated with the pathogenesis of FXS and can be monitored by depletion of components in EVs. These findings may improve the ability to diagnose developmental diseases associated with mitochondrial dysfunction, such as FXS and autism spectrum disorders (ASD).

Highlights

Fragile X syndrome (FXS), an inherited developmental disorder characterized by mental retardation and symptoms of autism spectrum disorders (ASD), is caused by transcriptional silencing of the FMR1 gene, which encodes fragile X mental retardation protein (FMRP) [1]
Quantitative real-time polymerase chain reaction results revealed that the mitochondrial DNA levels of mt-Co1 and 16S were significantly decreased in cortical tissues of Fmr1 KO mice (Figure 2)
As mitochondrial proteins have been detected in extracellular vesicles (EVs) purified from plasma [15], we examined whether mitochondrial dysfunction could be monitored by observing depletion of mitochondrial components in EVs secreted from astrocytes

Summary

Introduction

Fragile X syndrome (FXS), an inherited developmental disorder characterized by mental retardation and symptoms of autism spectrum disorders (ASD), is caused by transcriptional silencing of the FMR1 gene, which encodes fragile X mental retardation protein (FMRP) [1]. FMRP is an RNA-binding protein that is expressed primarily in neurons and astrocytes of the brain and associated with approximately 4% of transcripts, including those for mitochondrial proteins [2]. Developing neurons from Fmr KO mice show impaired dendritic maturation, altered expression of mitochondrial genes, fragmented mitochondria, impaired mitochondrial function, and increased oxidative stress [9]. It is not known if astrocytes from Fmr

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Results

Conclusion