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.
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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)
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Chemical References |
- 2-thiouridine
- Mitochondrial Proteins
- Thiouridine
- RNA, Transfer
- tRNA Methyltransferases
- TRMU protein, human
- Cysteine
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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)
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