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.