Childhood-onset mitochondrial encephalomyopathies are severe, relentlessly progressive conditions. However, reversible infantile respiratory chain deficiency (RIRCD), due to a homoplasmic mt-tRNAGlu mutation, and reversible infantilehepatopathy,duetotRNA5-methylaminomethyl-2-thiouridylatemethyltransferase(TRMU)deficiency, stand out by showing spontaneous recovery, and provide the key to treatments of potential broader relevance. Modification ofmt-tRNAGlu is a possible functional link between these two conditions, since TRMU is responsible for 2-thiouridylation of mt-tRNAGlu, mt-tRNALys and mt-tRNAGln. Here we show that down-regulation of TRMU in RIRCD impairs 2-thiouridylation and exacerbates the effect of themt-tRNAGlu mutation by triggering amitochondrial translation defect in vitro. Skeletal muscle of RIRCD patients in the symptomatic phase showed significantly reduced 2-thiouridylation. Supplementationwith L-cysteine,which is required for optimal TRMU function, rescued respiratory chain enzymeactivities inhumancell lines of patients withRIRCDas well asdeficientTRMU.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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