查看文章

Epitranscriptome modifications are required for structure and function of RNA and defects in these pathways have been associated with human disease. Here we identify the RNA target for the previously uncharacterized 5-methylcytosine (m⁵C) methyltransferase NSun3 and link m⁵C RNA modifications with energy metabolism. Using whole-exome sequencing, we identified loss-of-function mutations in NSUN3 in a patient presenting with combined mitochondrial respiratory chain complex deficiency. Patient-derived fibroblasts exhibit severe defects in mitochondrial translation that can be rescued by exogenous expression of NSun3. We show that NSun3 is required for deposition of m⁵C at the anticodon loop in the mitochondrially encoded transfer RNA methionine (mt-tRNA^Met). Further, we demonstrate that m⁵C deficiency in mt-tRNA^Met results in the lack of 5-formylcytosine (f⁵C) at the same tRNA position. Our …