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Lookup NU author(s): Dr Veronika Boczonadi, Dr Paul Smith, Dr Angela Pyle, Dr Aurora Gomez Duran, Professor Patrick Chinnery, Professor Rita HorvathORCiD
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Childhood-onset mitochondrial encephalomyopathies are severe, relentlessly progressive conditions. However, reversible infantile respiratory chain deficiency (RIRCD), due to a homoplasmic mt-tRNAGlu mutation, and reversible infantile hepatopathy, due to tRNA 5-methylaminomethyl-2-thiouridylate methyltransferase (TRMU) deficiency, stand out by showing spontaneous recovery, and provide the key to treatments of potential broader relevance. Modification of mt-tRNAGlu is a possible functional link between these two conditions, since TRMU is responsible for 2-thiouridylation of mt-tRNAGlu, mt-tRNALys and mt-tRNAGln. Here we show that down-regulation of TRMU in RIRCD impairs 2-thiouridylation and exacerbates the effect of the mt-tRNAGlu mutation by triggering a mitochondrial translation defect in vitro. Skeletal muscle of RIRCD patients in the symptomatic phase showed significantly reduced 2-thiouridylation. Supplementation with l-cysteine, which is required for optimal TRMU function, rescued respiratory chain enzyme activities in human cell lines of patients with RIRCD as well as deficient TRMU. Our results show that l-cysteine supplementation is a potential treatment for RIRCD and for TRMU deficiency, and is likely to have broader application for the growing group of intra-mitochondrial translation disorders.
Author(s): Boczonadi V, Smith PM, Pyle A, Gómez-Durán A, Schara U, Tulinius M, Chinnery PF, Horvath R
Publication type: Article
Publication status: Published
Journal: Human Molecular Genetics
Year: 2013
Volume: 22
Issue: 22
Pages: 4602-4615
Print publication date: 28/06/2013
ISSN (print): 0964-6906
ISSN (electronic): 1460-2083
Publisher: Oxford University Press
URL: http://dx.doi.org/10.1093/hmg/ddt309
DOI: 10.1093/hmg/ddt309
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