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

• 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.

Ämnesord

MEDICIN OCH HÄLSOVETENSKAP  -- Klinisk medicin -- Pediatrik (hsv//swe)

MEDICAL AND HEALTH SCIENCES  -- Clinical Medicine -- Pediatrics (hsv//eng)

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