TFB1M is a mitochondrial methyltransferase that catalyzes dimethylation of two conserved adenosine residues (A1583 and A1584) in the 12S rRNA loop, regulating small ribosomal subunit assembly and stability. Beyond its methyltransferase activity, TFB1M is required for basal mitochondrial DNA transcription through interaction with POLRMT and TFAM, and stimulates transcription independently of its methylation function. TFB1M plays a central role in mitochondrial energy metabolism. Loss of TFB1M in pancreatic β-cells impairs mitochondrial function, reducing ATP production and oxygen consumption, which compromises glucose-stimulated insulin secretion and leads to diabetes 1. A common TFB1M variant (rs950994) is associated with reduced insulin secretion and increased type 2 diabetes risk 2. In hepatocellular carcinoma, elevated TFB1M expression promotes tumor growth and metastasis by shifting metabolism from oxidative phosphorylation to glycolysis, and correlates with poor patient survival 3. A TFB1M variant (rs869120) was associated with estimated glomerular filtration rate in patients with type 1 diabetes 4. Mutational screening in Parkinson's disease found no significant association between TFB1M variants and disease risk 5. TFB1M expression is coordinately regulated with other mitochondrial biogenesis genes by nuclear respiratory factors and PGC-1 coactivators 6.