POLRMT encodes the human mitochondrial RNA polymerase, a single-subunit enzyme that catalyzes DNA-dependent RNA synthesis from mitochondrial DNA (mtDNA) using ribonucleoside triphosphates as substrates 1. The enzyme functions as a component of the mitochondrial transcription initiation complex alongside TFAM and TFB2M, where TFAM recruits POLRMT to specific promoters and TFB2M induces conformational changes enabling promoter opening 2. Beyond transcription, POLRMT exhibits DNA primase activity, synthesizing short RNA primers necessary for lagging-strand DNA replication at the origin of light-strand replication 1. POLRMT demonstrates high transcriptional fidelity with an error rate of approximately 2×10⁻⁵, comparable to replicative DNA polymerases 3. The enzyme's activity is regulated by post-translational modifications, including succinylation at lysine 622, which disrupts mtDNA binding and transcription factor interactions 4. Additionally, 7S RNA can inhibit transcription by inducing POLRMT dimerization, sequestering domains required for promoter recognition 5. Disease-causing variants in POLRMT cause combined oxidative phosphorylation deficiency 55, presenting with developmental delay, hypotonia, and intellectual disability due to impaired mitochondrial mRNA synthesis 1. POLRMT represents a therapeutic target, as specific small-molecule inhibitors show anti-tumor effects in cancer models 6.