MTERF1 is a mitochondrial transcription termination factor that recognizes and binds a 28 bp termination sequence within the tRNA(Leu) gene, immediately downstream of the 16S rRNA gene 1. The protein exhibits a superhelical topology complementary to DNA major groove binding, facilitating spontaneous diffusion on DNA during non-specific search mode before transitioning to high-affinity recognition 2. MTERF1 terminates transcription through a distinctive mechanism involving helix unwinding and base flipping of three nucleotides, with stepwise eversion stabilized by critical stacking interactions 13. This termination activity is polarized with highest specificity for light-strand-initiated transcripts 4. Beyond transcription termination, MTERF1 functions as a directional contrahelicase, blocking mtDNA replication fork progression through interaction with TWINKLE helicase 4. MTERF1 positively regulates mitochondrial gene transcription and oxidative phosphorylation activity, promoting ATP synthesis and cell proliferation through cyclin D1 upregulation 5. Under hypoxic conditions, MTERF1 operates downstream of focal adhesion kinase to modulate cell proliferation 6. Disease-associated G3249A and G3244A mutations eliminate termination by disrupting critical sequence recognition interactions 1, linking MTERF1 dysfunction to mitochondrial disease and age-related pathologies 7.