NSUN3

NSUN3 is a human gene encoding a mitochondrial RNA cytosine-5 methyltransferase of the NOP2/Sun (NSUN) family. The protein is directed to mitochondria by an N-terminal targeting sequence and uses S-adenosyl-L-methionine as a methyl donor to catalyze the formation of 5-methylcytosine at position 34 (the wobble position) of mitochondrial tRNA for methionine (tRNA(Met)). This modification, m5C34, is a prerequisite for subsequent oxidative modification of the same cytosine by the enzyme ABH1/ALKBH1, which converts it to 5-formylcytosine (f5C34). The NSUN3-ABH1 pathway thereby contributes to the formation of modified nucleotides in mt tRNA(Met) that enable proper decoding of certain codons in mitochondrial translation, including noncanonical readouts used in the mitochondrial genetic code.

Function and importance: NSUN3 activity is part of a broader system of mitochondrial tRNA modifications that regulate mitochondrial protein synthesis and respiratory chain function. By establishing m5C34 and facilitating its further modification to f5C34, NSUN3 plays a role in maintaining efficient mitochondrial translation and mitochondrial ribosome function.

Genetics and evolution: NSUN3 is conserved across metazoans as a member of the NSUN family of RNA methyltransferases. Its activity is linked to mitochondrial biology, and disruptions in mitochondrial tRNA modification pathways can contribute to mitochondrial dysfunction in experimental systems.

Clinical relevance: Direct disease associations for NSUN3 variants are not widely defined, but defects in mitochondrial tRNA modifications are broadly implicated in mitochondrial disorders. Research continues to elucidate the contribution of NSUN3 to human disease and mitochondrial health.