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Expression of expanded FMR1-CGG repeats alters mitochondrial miRNAs and modulates mitochondrial functions and cell death in cellular model of FXTAS

Gohel, D; Sripada, L; Prajapati, P; Currim, F; Roy, M; Singh, K; Shinde, A; ... Singh, R; + view all (2021) Expression of expanded FMR1-CGG repeats alters mitochondrial miRNAs and modulates mitochondrial functions and cell death in cellular model of FXTAS. Free Radical Biology and Medicine , 165 pp. 100-110. 10.1016/j.freeradbiomed.2021.01.038. Green open access

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Abstract

Fragile X-associated tremor/ataxia syndrome (FXTAS) is a progressive neurodegenerative disorder caused by an expansion of 55 to 200 CGG repeats located within 5′UTR of FMR1.These CGG repeats are transcribed into RNAs, which sequester several RNA binding proteins and alter the processing of miRNAs. CGG repeats are also translated into a toxic polyglycine-containing protein, FMRpolyG, that affects mitochondrial and nuclear functions reported in cell and animal models and patient studies. Nuclear-encoded small non-coding RNAs, including miRNAs, are transported to mitochondria; however, the role of mitochondrial miRNAs in FXTAS pathogenesis is not understood. Here, we analyzed mitochondrial miRNAs from HEK293 cells expressing expanded CGG repeats and their implication in the regulation of mitochondrial functions. The analysis of next generation sequencing (NGS) data of small RNAs from HEK293 cells expressing CGG premutation showed decreased level of cellular miRNAs and an altered pattern of association of miRNAs with mitochondria (mito-miRs). Among such mito-miRs, miR-320a was highly enriched in mitoplast and RNA immunoprecipitation of Ago2 (Argonaute-2) followed by Droplet digital PCR (ddPCR)suggested that miR-320a may form a complex with Ago2 and mitotranscripts. Finally, transfection of miR-320a mimic in cells expressing CGG permutation recovers mitochondrial functions and rescues cell death. Overall, this work reveals an altered translocation of miRNAs to mitochondria and the role of miR-320a in FXTAS pathology.

Type: Article
Title: Expression of expanded FMR1-CGG repeats alters mitochondrial miRNAs and modulates mitochondrial functions and cell death in cellular model of FXTAS
Location: United States
Open access status: An open access version is available from UCL Discovery
DOI: 10.1016/j.freeradbiomed.2021.01.038
Publisher version: https://doi.org/10.1016/j.freeradbiomed.2021.01.03...
Language: English
Additional information: This version is the author accepted manuscript. For information on re-use, please refer to the publisher’s terms and conditions.
Keywords: FXTAS, Mito-miRs, miR-320a, Mitotranscripts, Ago2, OXPHOS, Mitochondrial dysfunctions, Cell death
UCL classification: UCL
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Life Sciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Life Sciences > Div of Biosciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Life Sciences > Div of Biosciences > Cell and Developmental Biology
URI: https://discovery.ucl.ac.uk/id/eprint/10166416
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