TRMT61B is a mitochondrial N1-methyladenosine (m1A) methyltransferase with diverse RNA substrates. Primarily, it catalyzes m1A58 formation in mitochondrial tRNAs including tRNA(Leu), tRNA(Lys), and tRNA(Ser) 1, and mediates m1A947 modification of mitochondrial 16S rRNA, likely supporting mitoribosomal structure and function 2. Unlike cytoplasmic counterparts, TRMT61B functions as a homo-oligomer with bacterial evolutionary origins 1. Beyond mitochondrial roles, TRMT61B acts as an mRNA m1A methyltransferase, modifying diverse cytosolic mRNA sites with YMRA consensus motif preference 3, where m1A modifications variable affect translation and ribosome recruitment 3. In mitochondrial mRNA, TRMT61B-catalyzed m1A interferes with translation 4. Disease relevance includes pediatric tumors: TRMT61B rs4563180 G>C polymorphism associates with reduced Wilms tumor and hepatoblastoma susceptibility, with the C allele correlating with decreased TRMT61B expression 56. In adult cancers, TRMT61B serves as a biomarker for highly aneuploid tumors; its depletion induces senescence in low-aneuploidy cells or apoptosis in high-aneuploidy cells, reducing mitochondrial protein expression and function 7. TRMT61B appears dysregulated across oral squamous cell carcinoma, hepatoblastoma, and other malignancies 89.