NSUN3 is a mitochondrial tRNA methyltransferase that catalyzes 5-methylcytosine (m5C) formation at position 34 of mitochondrial tRNA(Met), initiating subsequent 5-formylcytosine (f5C) modification at the wobble position 123. This modification enables recognition of both AUG and AUA codons, expanding mitochondrial translation capacity 23. Mechanistically, NSUN3-mediated m5C modification stabilizes target mRNAs through enhanced mRNA stability. Beyond tRNA substrates, NSUN3 regulates expression of mitochondrial oxidative phosphorylation complex subunits and non-coding RNAs 45. Recent studies demonstrate NSUN3 modulates inflammatory responses in sepsis by stabilizing TAK1 and TIFA mRNAs through m5C modification 67. Disease relevance is substantial: biallelic NSUN3 mutations cause combined oxidative phosphorylation deficiency 48 with phenotypic heterogeneity ranging from isolated optic atrophy to severe early-onset multisystem mitochondrial disease 8. Tissue-specific NSUN3 loss impairs respiratory complex function and causes age-associated cardiac pathology 9. Additionally, NSUN3 dysregulation correlates with sepsis severity and serves as a diagnostic biomarker 10. Cancer cells exploit NSUN3-dependent mitochondrial modifications to enhance metabolic plasticity for metastatic dissemination 4, suggesting therapeutic potential for targeting this pathway.