METTL15 is a mitochondrial N4-methylcytidine (m4C) methyltransferase that catalyzes methylation at position C839 in mitochondrial 12S rRNA 12. This modification is essential for stabilizing 12S rRNA folding and facilitating assembly of mitochondrial small ribosomal subunits 12. METTL15 operates in a coordinated manner with assembly factor METTL17, acting at late assembly stages to mediate the transition from early to late pre-mitoribosome stages 3. The methylation process involves recruitment by ribosomal assembly factor hsRBFA and requires SAM as a cofactor 4. Loss of METTL15 function impairs mitochondrial protein synthesis, reduces steady-state levels of oxidative phosphorylation system components, and decreases mitochondrial respiration capacity 12. METTL15-knockout mice exhibit milder phenotypes than other mitochondrial translation apparatus mutants, demonstrating reduced blood glucose mobilization after exercise, decreased muscle performance, and impaired learning capabilities 5. METTL15 deficiency increases reactive oxygen species, alters membrane potential, and affects cellular metabolic state 4. While primarily functioning in mitochondrial bioenergetics, circRNA derived from METTL15 has been implicated in lung cancer progression through miR-1299/PDL1 axis regulation 6.