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

• Published in: Human molecular genetics 2013-11, Vol.22 (22), p.4602-4615
• Main Authors: Boczonadi, Veronika, Smith, Paul M, Pyle, Angela, Gomez-Duran, Aurora, Schara, Ulrike, Tulinius, Mar, Chinnery, Patrick F, Horvath, Rita
• Format: Article
• Language: English
• Subjects: Cell Line; Cysteine - metabolism; Electron transport; Gene Expression Regulation; Humans; Mitochondria - genetics; Mitochondrial Diseases - genetics; Mitochondrial Diseases - metabolism; Mitochondrial Diseases - pathology; Mitochondrial Encephalomyopathies - genetics; Mitochondrial Encephalomyopathies - metabolism; Mitochondrial Encephalomyopathies - pathology; Mitochondrial Proteins - genetics; Mitochondrial Proteins - metabolism; Muscle, Skeletal - metabolism; Mutation; Myoblasts - metabolism; Oxidative Phosphorylation; Pediatrics; Pediatrik; Protein Biosynthesis - genetics; Protein Biosynthesis - physiology; RNA, Transfer - genetics; RNA, Transfer - metabolism; Thiouridine - analogs & derivatives; Thiouridine - metabolism; tRNA Methyltransferases - genetics; tRNA Methyltransferases - metabolism
• ISSN: 0964-6906; 1460-2083; 1460-2083
• DOI: 10.1093/hmg/ddt309

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.