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

Abstract：

:Childhood-onset mitochondrial encephalomyopathies are severe, relentlessly progressive conditions. However, reversible infantile respiratory chain deficiency (RIRCD), due to a homoplasmic mt-tRNA(Glu) 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-tRNA(Glu) is a possible functional link between these two conditions, since TRMU is responsible for 2-thiouridylation of mt-tRNA(Glu), mt-tRNA(Lys) and mt-tRNA(Gln). Here we show that down-regulation of TRMU in RIRCD impairs 2-thiouridylation and exacerbates the effect of the mt-tRNA(Glu) 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.

journal_name

Hum Mol Genet

journal_title

Human molecular genetics

authors

Boczonadi V,Smith PM,Pyle A,Gomez-Duran A,Schara U,Tulinius M,Chinnery PF,Horvath R

doi

10.1093/hmg/ddt309

subject

Has Abstract

pub_date

2013-11-15 00:00:00

pages

4602-15

issue

22

eissn

0964-6906

issn

1460-2083

pii

ddt309

journal_volume

22

pub_type

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