NSUN4

NSUN4 (NOP2/Sun domain family member 4) is a mitochondrial RNA methyltransferase in humans and other eukaryotes. It belongs to the NSUN family of cytosine-5 RNA methyltransferases and is targeted to the mitochondrial matrix, where it participates in the modification of mitochondrial RNA.

Function and mechanism: NSUN4 catalyzes the formation of 5-methylcytosine (5-mmC) at specific cytosine residues within mitochondrial RNA, notably in the 12S ribosomal RNA. It forms a functional complex with MTERF4 (mitochondrial transcription termination factor 4). The MTERF4-NSUN4 complex has dual roles: it acts as an RNA methyltransferase in mitochondria and also serves as a ribosome assembly factor that promotes maturation of the small subunit of the mitochondrial ribosome. This complex coordinates rRNA modification with ribosome biogenesis, supporting efficient mitochondrial translation. Methyltransferase activity uses S-adenosyl-L-methionine as the methyl donor.

Localization and evolution: NSUN4 contains mitochondrial targeting signals and localizes to mitochondria. It is conserved across eukaryotes, reflecting a fundamental role in mitochondrial RNA processing and ribosome function.

Clinical significance: Because NSUN4 is involved in mitochondrial rRNA modification and ribosome assembly, loss or alteration of its function can impair mitochondrial protein synthesis and respiration, contributing to mitochondrial dysfunction. In model systems, disruption of NSUN4 or the MTERF4-NSUN4 axis leads to defects in mitoribosome assembly and translation, underscoring the importance of this pathway for mitochondrial function.