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Altered 2-thiouridylation impairs mitochondrial translation in reversible infantile respiratory chain deficiency

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.

Publication metadata

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


DOI: 10.1093/hmg/ddt309


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Funder referenceFunder name
Wellcome Trust Centre for Mitochondrial Research
309548European Research Council
G1000848Medical Research Council (UK)