RNA nucleotide repeats induce mitochondrial dysfunction and the ribosome-associated quality control

Nucleotide repeat sequences are prevalent in the genome and expansion of these sequences is associated with more than 40 neuromuscular disorders. To understand the pathogenic mechanisms underlying RNA-repeat toxicity, we performed a genetic screen in a Caenorhabditis elegans model expressing an expanded CUG repeat specifically in the muscle. Here, we show that expression of this RNA repeat impairs motility by mitochondrial dysfunction, disrupting mitochondrial morphology and respiration. The phenotype is dependent on the RNA-binding factor MBL-1 and requires factors from the ribosome-associated protein quality control complex. Furthermore, Coenzyme Q supplementation rescued the motility impairment and all of the mitochondrial phenotypes. Together, our data reveal the importance of mitochondrial dysfunction in the molecular pathogenesis of RNA repeat expansion disorders. ### Competing Interest Statement The authors have declared no competing interest. * ctl : catalase CoQ : Coenzyme Q DM1 : myotonic dystrophy type 1 DMPK : dystrophia myotonica-protein kinase gene Egl phenotype : egg-laying defective phenotype EtOH : ethanol ETC : electron transport chain EV : empty vector (control RNAi) GD : E. coli [ ubiG ::Kan, zei ::Tn 10 dTet] HT115 : E. coli [F-, mcrA, mcrB, IN(rrnD-rrnE)1, rnc14::Tn10(DE3 lysogen: lacUV5 promoter -T7 polymerase] LC-MS : liquid chromatography coupled to mass spectrometry mtDNA : mitochondrial DNA MBL-1 : muscleblind splicing regulator homolog MBNL : muscleblind-like splicing regulator NAC : N-acetylcysteine OCR : oxygen consumption rate OP50 : E. coli strain RNAi : RNA interference OXPHOS : oxidative phosphorylation ROS : reactive oxygen species RQC : ribosome-associated quality control SOD : superoxide dismutase SRC : spare respiratory capacity UPRmt : mitochondrial unfolded protein response