- Mitochondrial RNA polymerase (POLRMT) is a specialized, single-subunit enzyme responsible for transcribing mitochondrial DNA (mtDNA) within the mitochondria of eukaryotic cells.
- Unlike the multi-subunit nuclear RNA polymerases (Pol I, II, and III), POLRMT more closely resembles bacteriophage RNA polymerases, particularly T7 RNA polymerase, reflecting the bacterial origin of mitochondria through endosymbiosis. Despite its structural simplicity, POLRMT performs complex regulatory and transcriptional functions vital for mitochondrial gene expression and energy production.
- Mitochondria possess their own small, circular genome, which encodes 13 essential protein subunits of the oxidative phosphorylation (OXPHOS) complexes, along with 22 transfer RNAs (tRNAs) and 2 ribosomal RNAs (rRNAs) required for mitochondrial protein synthesis. POLRMT transcribes the entire mitochondrial genome, initiating from specific promoter regions located on the heavy (H) and light (L) strands of mtDNA. These promoters—HSP1, HSP2, and LSP (Heavy Strand Promoters 1 and 2, and Light Strand Promoter)—are recognized with the assistance of two essential transcription factors: TFAM (Transcription Factor A, Mitochondrial) and TFB2M (Transcription Factor B2, Mitochondrial). TFAM binds and bends mitochondrial DNA at the promoter site, facilitating recruitment of POLRMT and TFB2M, which together initiate transcription.
- Once engaged, POLRMT synthesizes RNA in the 5′ to 3′ direction using ribonucleotide triphosphates (NTPs). Mitochondrial transcription is unique in that POLRMT generates long polycistronic transcripts, which encompass multiple genes on a single strand. These transcripts are subsequently processed by endonucleases into individual mRNAs, tRNAs, and rRNAs in a tightly coordinated fashion. The presence of tRNA sequences between coding regions serves as punctuation marks for RNA cleavage, a mechanism known as the “tRNA punctuation model.”
- In addition to transcription, POLRMT also plays a role in mitochondrial DNA replication. It synthesizes short RNA primers at the origin of replication (OriH), which are used by the mitochondrial DNA polymerase (Pol γ) to initiate replication. Thus, POLRMT functions as both a transcription and replication initiator within mitochondria, linking the processes of gene expression and genome maintenance.
- POLRMT activity is finely regulated in response to the cell’s metabolic needs and environmental signals. Mitochondrial transcription can be influenced by the availability of transcription factors, ATP levels, mitochondrial membrane potential, and nuclear-encoded regulatory proteins. Under stress or pathological conditions, POLRMT function may be disrupted, leading to impaired expression of respiratory chain components and consequent mitochondrial dysfunction, which is implicated in various human diseases including neurodegenerative disorders, metabolic syndromes, and mitochondrial myopathies.
