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.

• Authors: Veronika Boczonadi, Paul M Smith, Angela Pyle, Aurora Gomez-Duran, Ulrike Schara, Mar Tulinius, Patrick F Chinnery, Rita Horvath
• Journal: Human molecular genetics (Hum Mol Genet) Vol. 22 Issue 22 Pg. 4602-15 (Nov 15 2013) ISSN: 1460-2083 [Electronic] England
• PMID: 23814040 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• 2-thiouridine
• Mitochondrial Proteins
• Thiouridine
• RNA, Transfer
• tRNA Methyltransferases
• TRMU protein, human
• Cysteine

Topics

• Cell Line
• Cysteine (metabolism)
• Gene Expression Regulation
• Humans
• Mitochondria (genetics)
• Mitochondrial Diseases (genetics, metabolism, pathology)
• Mitochondrial Encephalomyopathies (genetics, metabolism, pathology)
• Mitochondrial Proteins (genetics, metabolism)
• Muscle, Skeletal (metabolism)
• Mutation
• Myoblasts (metabolism)
• Oxidative Phosphorylation
• Protein Biosynthesis (genetics, physiology)
• RNA, Transfer (genetics, metabolism)
• Thiouridine (analogs & derivatives, metabolism)
• tRNA Methyltransferases (genetics, metabolism)