RNA nucleotide repeats induce mitochondrial dysfunction and the ribosome-associated quality control
RNA nucleotide repeats induce mitochondrial dysfunction and the ribosome-associated quality control
Abstract 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.
Othman Alaa、Harju Anu-Mari、Eriksson Ove、Brand?o Ana、Garcia Susana M. D. A.、Teixeira Joana、Battersby Brendan J.
Institute of Molecular Systems Biology, ETH ZurichInstitute of Biotechnology, HiLIFE, University of HelsinkiBiochemistry/Developmental Biology, Faculty of Medicine, University of HelsinkiInstitute of Biotechnology, HiLIFE, University of HelsinkiInstitute of Biotechnology, HiLIFE, University of HelsinkiInstitute of Biotechnology, HiLIFE, University of HelsinkiInstitute of Biotechnology, HiLIFE, University of Helsinki
基础医学分子生物学神经病学、精神病学
CUG repeatsmyotonic dystrophyRNA repeat toxicitymitochondrial dysfunctionCoenzyme QCaenorhabditis elegansribosome-associated quality control
Othman Alaa,Harju Anu-Mari,Eriksson Ove,Brand?o Ana,Garcia Susana M. D. A.,Teixeira Joana,Battersby Brendan J..RNA nucleotide repeats induce mitochondrial dysfunction and the ribosome-associated quality control[EB/OL].(2025-03-28)[2025-06-06].https://www.biorxiv.org/content/10.1101/2021.09.24.461665.点此复制
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