Nsun3, or NOP2/Sun RNA methyltransferase 3, is a mitochondrial methyltransferase. It is crucial for initiating 5-formylcytidine (f5C) biogenesis in mitochondrial tRNA(Met), specifically methylating cytosine 34 (C34) at the wobble position of mt-tRNAMet. This modification is essential for mitochondrial translation, as it enables the recognition of non-conventional AUA codons encoding methionine. Nsun3-related functions are involved in various biological processes, including embryonic development and metabolic regulation [3,4].

In mice, whole-body Nsun3 knockout embryos die between E10.5 and E12.5, highlighting its essentiality for embryonic development. Heart-specific Nsun3 knockout (Nsun3HKO) mice show enlarged heart mitochondria with fragmented cristae, enhanced heart contraction, and age-associated mild heart enlargement. The enzymatic activities of respiratory complexes decrease in Nsun3HKO hearts, especially in older mice, despite no down-regulation of mitochondrial mRNAs encoding respiratory complex subunits [1]. In human studies, mutations in NSUN3 are associated with mitochondrial diseases, such as early-onset mitochondrial encephalomyopathy, seizures, and inherited optic neuropathy [2,5].

In conclusion, Nsun3 is vital for mitochondrial tRNA modification, which is essential for mammalian embryonic development and mitochondrial function. Mouse knockout models have been instrumental in revealing its role in embryonic development and age-related heart tissue aberration. Human studies further link Nsun3 mutations to mitochondrial-related diseases, emphasizing its significance in understanding disease mechanisms.